Biaryl spiroaminooxazoline analogues as Alpha2C adrenergic receptor modulators

ABSTRACT

In its many embodiments, the present invention provides a novel class of biaryl spiroaminooxazoline analogues as modulators of α2C adrenergic receptor agonists, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more conditions associated with the α2C adrenergic receptors using such compounds or pharmaceutical compositions.

RELATED APPLICATIONS

This application claims benefit of U.S. provisional application U.S.Ser. No. 61/103,409, filed Oct. 7, 2008, herein incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to biaryl spiroaminooxazoline analoguesuseful as alpha-2C (or “α2C”) adrenergic receptor modulators, methodsfor making these compounds, pharmaceutical compositions containing thecompounds, and methods of treatment and prevention using the compoundsand compositions to treat disease states associated with the modulationof the alpha-2C receptor, such as congestion (including nasal),migraine, congestive heart failure, cardiac ischemia, glaucoma,stress-induced urinary incontinence, Alzheimer's disease, Parkinson'sdisease, attention deficit hyperactivity disorder, pain and psychoticdisorders (e.g., depression and schizophrenia).

BACKGROUND OF THE INVENTION

The initial classification of adrenergic receptors into α- andβ-families was first described by Ahlquist in 1948 (Ahlquist R P, “AStudy of the Adrenergic Receptors,” Am. J. Physiol. 153:586-600 (1948)).Functionally, the α-adrenergic receptors were shown to be associatedwith most of the excitatory functions (vasoconstriction, stimulation ofthe uterus and pupil dilation). β-adrenergic receptors were implicatedin vasodilation, bronchodilation and myocardial stimulation (Lands etal., “Differentiation of Receptor Systems Activated by Sympathomimeticamines,” Nature 214:597-598 (1967)). Since this early work, α-adrenergicreceptors have been subdivided into α1- and α2-adrenergic receptors.Cloning and expression of α-adrenergic receptors have confirmed thepresence of multiple subtypes of both α1-(α1A, α1B, α1D) and α2-(α2A,α2B, α2C) adrenergic receptors (Michel et al., “Classification ofα₁-Adrenoceptor Subtypes,” Naunyn-Schmiedeberg's Arch. Pharmacol,352:1-10 (1995); Macdonald et al., “Gene Targeting—Homing in onα₂-Adrenoceptor-Subtype Function,” TIPS, 18:211-219 (1997)).

Current therapeutic uses of α-2 adrenergic receptor drugs involve theability of those drugs to mediate many of the physiological actions ofthe endogenous catecholamines. There are many drugs that act on thesereceptors to control hypertension, intraocular pressure, eye reddeningand nasal congestion and induce analgesia and anesthesia.

α2 adrenergic receptors can be found in the rostral ventrolateralmedulla, and are known to respond to the neurotransmitter norepinephrineand the antihypertensive drug clonidine to decrease sympathetic outflowand reduce arterial blood pressure (Bousquet et al., “Role of theVentral Surface of the Brain Stem in the Hypothesive Action ofClonidine,” Eur. J. Pharmacol., 34:151-156 (1975); Bousquet et al.,“Imidazoline Receptors: From Basic Concepts to Recent Developments,”26:S1-S6 (1995)). Clonidine and other imidazolines also bind toimidazoline receptors (formerly called imidazoline-guanidinium receptivesites or IGRS) (Bousquet et al., “Imidazoline Receptors: From BasicConcepts to Recent Developments,” 26:S1-S6 (1995)). Some researchershave speculated that the central and peripheral effects of imidazolinesas hypotensive agents may be related to imidazoline receptors (Bousquetet al., “Imidazoline Receptors: From Basic Concepts to RecentDevelopments,” 26:S1-S6 (1995); Reis et al., “The Imidazoline Receptor:Pharmacology, Functions, Ligands, and Relevance to Biology andMedicine,” Ann. N.Y. Acad. Sci., 763:1-703 (1995).

Compounds having adrenergic activity are well-known in the art and aredescribed in numerous patents and scientific publications. It isgenerally known that adrenergic activity is useful for treating animalsof the mammalian species, including humans, for curing or alleviatingthe symptoms and conditions of numerous diseases and conditions. Inother words, it is generally accepted in the art that pharmaceuticalcompositions having an adrenergic compound or compounds as the activeingredient are useful for treating, among other things, glaucoma,chronic pain, migraines, heart failure, and psychotic disorders (e.g.,schizophrenia).

For example, published PCT application WO 02/076950 discloses compoundshaving α2 agonist activity of the following general formula:

Other publications disclosing similar compounds includes WO 01/00586, WO99/28300, U.S. Pat. No. 6,841,684 B2 and US 2003/0023098 A1.

Another class of compounds having α2-agonist properties is disclosed inU.S. Pat. No. 5,658,938, and has the following general formula:

wherein n=1-2, R¹-R³ represent hydrogen, halogen hydroxy, alkyl oralkoxy, and R⁵ is hydrogen or alkyl.

Another class of compounds reported to have affinity for α2 receptorsincludes the following two compounds (Bagley et. al., Med. Chem. Res.1994, 4:346-364):

It is also known that compounds having adrenergic activity, such as α2Aagonists, may be associated with undesirable side effects. Examples ofsuch side effects include hyper- and hypotension, sedation, locomotoractivity, psychotic disorders (e.g., schizophrenia).

Another class of compounds reported to have affinity for α2 receptorsincludes the following two compounds (Miller et. al., J. Med. Chem.1994, 37:2328-2333; J. Med. Chem. 1996, 39:3001-3013; J. Med. Chem.1997, 37:3014-3024):

Another class of indane and tetrahyrdonaphthalene type compounds havingα2-agonist properties is disclosed in PCT application WO 97/12874 andWO20040506356. This class has the following general formula:

wherein n=0-1, X is 1 or 2 carbon units, R₄ is H, OH, alkyl, or alkoxy,R₅ may be taken together with R⁴ to form a carbonyl, and R⁶-R⁸═H, OH,SH, alkyl, alkenyl, cycloalkyl, alkoxy, hydroxyalkyl, alkylthio,alkylthiol, halo, CF₃, NO₂, or alkylamino. This class specificallyincludes MPV-2426 (fadolmidine) and its prodrug esters:

wherein R is optionally substituted lower alkyl, aryl, cycloalkyl,heteroaryl, lower alkylamino, and saturated 5- or 6-memberedheterocyclic groups containing 1 or 2 N atoms.

Further, other classes of compounds that exhibit functional selectivityfor the alpha 2C receptor have been discovered. Application U.S. Ser.No. 11/508,458, filed Aug. 23, 2006, discloses indoline compounds thatpossess this activity and application U.S. Ser. No. 11/508,467, filed onthe same date, describes morpholine compounds that are functionallyselective of the alpha 2C receptor. CIP applications of theseapplications have been filed; the Ser. Nos. 11/705,673 and 11/705,683,both filed on Feb. 13, 2009.

Additional applications that have been filed by Schering-Plough anddisclose alpha2C receptor agonists include applications WO 2008/100480(PCT/US2008/001808); WO 2008/100459 (PCT/US2008/001770) and WO2008/100456 (PCT/US2008/001765.

Compounds that act as antagonists of the alpha-2C receptor are alsoknown in the art. Hoeglund et al. describe quinoline derivatives thatare said to be potent and selective alpha 2C antagonists and said to beuseful in treating “certain psychiatric disorders such as depression andschizophrenia” (Hoeglund et al., J. Med. Chem 49:6351-6363 (2006)). WO2001/64645 to Orion Corp. also describes quinoline derivatives that arealpha-2C receptor antagonists and indicates that these compounds areuseful for the treatment of conditions of the pheripheric or CNS system,including treating depression, anxiety, post traumatic stress disorder,schizophrenia, Parkinson's disease and other movement disorders, anddementias (e.g., Alzheimer's disease). WO 2003/082825, also to OrionCorp., indicates alpha-2C receptor antagonists have utility in treatingsymptoms of disorders and conditions with sensorimotor-gating deficits.Selliner et al., indicate thatacridin-9-yl-[4-(4-methylpiperazinal-1-yl)phenyl]amine is a highlyselective alpha-2C adrenergic receptor antagonist and may be usefulintreating neuropsychiatric disorders (Salliner et al., British J.Pharmacol. 150:391-402 (2007)).

It is also known that compounds having adrenergic activity, such as α2Aagonists, may be associated with undesirable side effects. Examples ofsuch side effects include hyper- and hypotension, sedation, locomotoractivity, and body temperature variations.

Cordi et al. in U.S. Pat. Nos. 5,436,261, 5,486,532 and 5,648,374describe benzospiroalkene heterocyclic compounds of the general formula

that are said to be useful as α2-adrenergic agonists; in the compoundsdescribed therein the definition of X includes —(CH₂)₂—, —O—, —O—CH₂—,and —S—CH₂—; of Y includes —O—, —S—, and —N(R₆)—; and of R₅ includeshydrogen or an amino group. Cordi et al. also disclosespiro[1,3-diazacyclopent-1-ene)5,2′-(1′,2′,3′,4′-tetrahydronaphthylene)]or spiro-imidazolines compounds such as

in J. Med. Chem. 1994, 38:4056-4069 as α-adrenergic agonists. WO2006/080890 discloses that this compound may be used in combinationswith other agents to prevent biofouling organisms.

U.S. Pat. No. 6,673,337 describes and claims an ophthalmic compositioncomprising an alpha-2C agonist component and a solubility enhancingcomponent other than cyclodextrin. The patent does not specificallydescribe alpha-2C receptor agonists.

It has been discovered in accordance with the present invention that theinventive compounds act as modulators of the alpha-2C receptor (i.e.,they can act as alpha-2C receptor agonists or as alpha-2C receptorantagonists) and are useful in treating disorders modulated by thealpha-2C receptor.

There is a need for new compounds, formulations, treatments andtherapies to treat diseases and disorders associated with α2C adrenergicreceptors. Further, there is a need for alpha-2C receptor modulatorsthat minimize adverse side effects, such as those associated with thealpha-2A receptor subtype (viz., blood pressure or sedation). It is,therefore, an object of this invention to provide compounds useful inthe treatment or prevention or amelioration of such diseases anddisorders.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofheterocyclic compounds that are modulators of the α2C adrenergicreceptor, or metabolites, stereoisomers, salts, solvates or polymorphsthereof, methods of preparing such compounds, pharmaceuticalcompositions comprising one or more such compounds, methods of preparingpharmaceutical formulations comprising one or more such compounds, andmethods of treatment, prevention, inhibition or amelioration of one ormore conditions associated with α2C receptors using such compounds orpharmaceutical compositions.

In one aspect, the present application discloses a compound, orpharmaceutically acceptable salts or metabolites, solvates, prodrugs orpolymorphs of said compound, said compound having the general structureshown in Formula I

wherein:

J¹, J², J³ and J⁴ are independently —N—, —N(O)—, or —C(R²)—;

X is —C(R⁶)(R^(6′))—, —N(R^(6′))—, —O— or —S—;

W is —N(R¹⁵)—, —O— or —S—;

Z is independently selected from the group consisting of H, —OH, halo,—CN, —NO₂, —S(O)_(p)R⁷, —NR⁷R^(7′), —[C(R^(a))(R^(b))]_(q)YR^(7′),—[C(R^(a))(R^(b))]_(q)N(R⁷)YR^(7′), —[C(R^(a))(R^(b))]_(q)OYR^(7′), and—(CH₂)_(q)ON═CR⁷R^(7′), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionallysubstituted with at least one (preferably 1 to 5, more preferably 1 to3) R⁵;

-   -   wherein        is a single or double bond provided that when W is —O— or —S—,        the double bond is present between N and the 2-position, and        when W is —N(R¹⁵)—, the double bond is present between the N and        the 2-position or W and the 2-position, but cannot form 2        contiguous double bonds;

R¹ is a ring selected from the group consisting of cycloalkyl,cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl, eachof which is optionally substituted with at least one (preferably 1 to 5,more preferably 1 to 3) R¹²;

R² is absent or independently selected from the group consisting of H,halo, —CN, —NO₂, —OH, —S(O)_(p)R⁷, —NR⁷R^(7′),—[C(R^(a))(R^(b))]_(q)YR^(7′), —[C(R^(a))(R^(b))]_(q)N(R⁷)YR^(7′),—[C(R^(a))(R^(b))]_(q)N(R⁷)CN, —[C(R^(a))(R^(b))]_(q)OYR^(7′), and—(CH₂)_(q)ON═CR⁷R^(7′), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionallysubstituted with at least one (preferably 1 to 5, more preferably 1 to3) R⁵;

Y is selected from the group consisting of a bond, —C(═O)—, —C(═O)NR⁷—,—C(═O)O—, —C(═O)N(R^(c))—O—, —C(═NR⁷)—, —C(═NOR⁷)—, —C(═NR⁷)NR⁷—,—C(═NR⁷)NR⁷O—, —C(═N—CN)—, —S(O)_(p)—, —SO₂NR⁷—, and —C(═S)NR⁷—;

-   -   wherein R^(a) and R^(b) are independently selected from the        group consisting of H, alkyl, alkoxy, and halo, and    -   R^(c) is H or alkyl;

R³ is independently selected from the group consisting of H, —OH, halo,—CN, —NO₂, —S(O)_(p)R⁷, —NR⁷R^(7′), —S(O)_(p)NR⁷R^(7′), and (═O), andalkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups optionally substituted with at least one(preferably 1 to 5, more preferably 1 to 3) R⁵, provided that when w is3, no more than 2 of the R³ groups may be (═O);

R⁴ is independently selected from the group consisting of H, D, —OH,halo, —CN, —S(O)_(p)R⁷, —NR⁷R^(7′) and —S(O)_(p)NR⁷R^(7′), and alkyl,deuterated alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one (preferably 1 to 5, more preferably 1 to 3) R⁵;

R^(4′) is independently selected from the group consisting of H, D,halo, —OH, and alkyl, deuterated alkyl and alkoxy; or

-   -   R⁴ and R^(4′) may be taken together to form (═O), provided that        when m>1, there is no more than 1 (═O) group;

R⁵ is independently selected from the group consisting of H, halo, —OH,—CN, —NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷, and alkyl, alkoxy, alkenyl,alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups,each of which is optionally substituted with at least one (preferably 1to 5, more preferably 1 to 3) of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and—S(O)_(p)R⁷ substituents and/or 1 or 2 (═O) groups,

R⁶ is selected from the group consisting of H, —OH, halo, —CN, —NO₂,—S(O)_(p)R⁷, —NR⁷R^(7′), —S(O)_(p)NR⁷R^(7′), —C(O)—R¹⁰, —O(O)—OR¹⁰, and—C(O)—N(R⁷)R¹⁰, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each ofwhich is optionally substituted with at least one (preferably 1 to 5,more preferably 1 to 3) of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and—S(O)_(p)R⁷ substituents and/or 1 or 2 (═O) groups, and —C(═O)R⁷,—C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and —SO₂NR⁷R^(7′);

R^(6′) is selected from the group consisting of H, —S(O)_(p)R⁷,—S(O)_(p)NR⁷R^(7′), —C(O)—R¹⁰, —C(O)—OR¹⁰, —C(O)—N(R⁷)R¹⁰ and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one (preferably 1 to 5, more preferably 1 to 3) of halo, —OH,—CN, —NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷ and/or 1 or 2 (═O) groupssubstituents, and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and—SO₂NR⁷R^(7′); or

-   -   R⁶ and R^(6′) may be taken together to form (═O);

R⁷ is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl,cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted one or more times(preferably 1 to 5, more preferably 1 to 3) by R¹²;

R^(7′) is independently selected from the group consisting of H andalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl,cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted one or more times(preferably 1 to 5, more preferably 1 to 3) by R¹²; or

-   -   a) when a variable is —NR⁷R^(7′), —C(O)NR⁷R^(7′) or        —SO₂NR⁷R^(7′), R⁷ and R^(7′) together with the nitrogen atom to        which they are attached independently form a 3- to 8-membered        heterocyclyl, heterocyclenyl or heteroaryl ring having, in        addition to the N atom, 1 or 2 additional hetero atoms        independently selected from the group consisting of O, N,        —N(R⁹)— and S, wherein said rings are optionally substituted by        1 to 5 independently selected R¹² moieties and/or 1 or 2 (═O)        groups, or    -   b) when a variable is —(CH₂)_(q)ON═CR⁷R^(7′), R⁷ and R^(7′)        together with the carbon atom to which they are attached        independently form a 3- to 8-membered cycloalkyl, cycloalkenyl,        aryl, heterocyclyl, heterocyclenyl or heteroaryl ring, wherein        said heterocyclyl, heterocyclenyl or heteroaryl rings have 1-3        heteroatoms which are independently selected from the group        consisting of O, N, —N(R⁹)— and S, wherein said rings are        optionally substituted by 1 to 5 independently selected R¹²        moieties and/or 1 or 2 (═O) groups,

R⁹ is independently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, and —S(O)_(p)—R¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one (preferably 1 to 5, morepreferably 1 to 3) of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹substituents and/or 1 or 2 (═O) groups; and

R¹⁰ is independently selected from the group consisting of H, and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups groups, each of which is optionally substitutedwith at least one (preferably 1 to 5, more preferably 1 to 3) of halo,—OH, —CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹ substituents and/or 1 or 2(═O);

R¹¹ is a moiety independently selected from the group consisting of Hand alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, each of which is optionallysubstituted by at least one (preferably 1 to 5, more preferably 1 to 3)substituent independently selected from the group consisting of halo,—OH, —CN, —NO₂, —N(R^(11′))₂, and —S(O)_(p)R^(11′) and/or 1 or 2 (═O)groups;

R^(11′) is independently selected from the group consisting of H, alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R¹² is independently selected from the group consisting of H, halo, —OH,—CN, —NO₂, —N(R¹¹)₂, —C(O)—OR¹⁴, —N(R¹⁴)—C(O)—R¹⁴, —N(R¹⁴)—C(O)₂—R¹⁴,—C(O)—N(R¹¹)₂, —N(R¹⁴)—S(O)₂—R¹¹, —S(O)₂—N(R¹¹)₂ and —S(O)_(p)R¹¹ and/or1 or 2 (═O) groups, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl,heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl,heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl,heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy,and heterocyclenylalkoxy groups, each of which in turn is optionallysubstituted by at least once (preferably 1 to 5, more preferably 1 to 3)by a substituent selected from the group consisting of H, alkyl,haloalkyl, halo, —OH, optionally substituted alkoxy, optionallysubstituted aryloxy, optionally substituted cycloalkoxy, optionallysubstituted heteroaryloxy, optionally substituted heterocyclenyloxy,—CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹ and/or 1 or 2 (═O) groups, whereinsaid optionally substituted alkoxy, aryloxy, optionally substitutedcycloalkoxy, optionally substituted heteroaryloxy, and heterocyclenyloxywhen substituted are substituted one or more (preferably 1 to 5, morepreferably 1 to 3) times by R¹¹;

R¹⁴ is independently H, alkyl, or aryl;

R¹⁵ is absent (i.e., the nitrogen and the 2-position carbon atom form a—N═C(Z)-bond) independently selected from the group consisting of H,—C(O)—R¹⁰, —C(O)—OR¹⁰, —C(O)—N(R⁷)(R^(7′)), and —S(O)_(p)—R¹⁰, SO₂—NR⁷R⁷and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups, each of which is optionallysubstituted with at least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and—S(O)_(p)R⁷ and/or 1 or 2 (═O) groups substituents, and —C(═O)R⁷,—C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and —SO₂NR⁷R⁷;

q is independently an integer from 0-10;

n is independently an integer from 0-2;

m is independently an integer from 1-3;

p is independently an integer from 0-2; and

w is an integer from 0-3.

In another aspect, the present application discloses a compound, orpharmaceutically acceptable salts or metabolites, solvates, prodrugs orpolymorphs of said compound, said compound having the general structureshown in Formula II

wherein:

J¹, J², J³ and J⁴ are independently —N—, —N(O)—, or —C(R²)—;

X is —C(R⁶)(R^(6′))—, —N(R^(6′))—, —O— or —S—;

R¹ is a ring selected from the group consisting of cycloalkyl,cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl, eachof which is optionally substituted with at least one (preferably 1 to 5,more preferably 1 to 3) R¹²;

R² is absent or independently selected from the group consisting of H,halo, —CN, —NO₂, —OH, —S(O)_(p)R⁷, —NR⁷R^(7′),—[C(R^(a))(R^(b))]_(q)YR^(7′), —[C(R^(a))(R^(b))]_(q)N(R⁷)YR^(7′),—[C(R^(a))(R^(b))]_(q)N(R⁷)CN, —[C(R^(a))(R^(b))]_(q)OYR^(7′), and—(CH₂)_(q)ON═CR⁷R^(7′), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionallysubstituted with at least one (preferably 1 to 5, more preferably 1 to3) R⁵;

Y is selected from the group consisting of a bond, —C(═O)—, —C(═O)NR⁷—,—C(═O)O—, —C(═O)N(R^(c))—O—, —C(═NR⁷)—, —C(═NOR⁷)—, —C(═NR⁷)NR⁷—,—C(═NR⁷)NR⁷O—, —C(═N—CN)—, —S(O)_(p)—, —SO₂NR⁷—, and —C(═S)NR⁷—;

-   -   wherein R^(a) and R^(b) are independently selected from the        group consisting of H, alkyl, alkoxy, and halo, and    -   R^(c) is H or alkyl;

R³ is independently selected from the group consisting of H, —OH, halo,—CN, —NO₂, —S(O)_(p)R⁷, —NR⁷R^(7′), —S(O)_(p)NR⁷R^(7′), and (═O), andalkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups optionally substituted with at least one(preferably 1 to 5, more preferably 1 to 3) R⁵, provided that when w is3, no more than 2 of the R³ groups may be (═O);

R⁴ is independently selected from the group consisting of H, D, —OH,halo, —CN, —S(O)_(p)R⁷, —NR⁷R^(7′) and —S(O)_(p)NR⁷R^(7′), and alkyl,deuterated alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one (preferably 1 to 5, more preferably 1 to 3) R⁵;

R^(4′) is independently selected from the group consisting of H, D,halo, —OH, and alkyl, deuterated alkyl and alkoxy; or

-   -   R⁴ and R^(4′) may be taken together to form (═O);

R⁵ is independently selected from the group consisting of H, halo, —OH,—CN, —NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷, and alkyl, alkoxy, alkenyl,alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups,each of which is optionally substituted with at least one (preferably 1to 5, more preferably 1 to 3) of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and—S(O)_(p)R⁷ substituents and/or 1 or 2 (═O) groups,

R⁶ is selected from the group consisting of H, —OH, halo, —CN, —NO₂,—S(O)_(p)R⁷, —NR⁷R^(7′), —S(O)_(p)NR⁷R^(7′), —C(O)—R¹⁰, —C(O)—OR¹⁰, and—C(O)—N(R⁷)R¹⁰, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each ofwhich is optionally substituted with at least one (preferably 1 to 5,more preferably 1 to 3) of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and—S(O)_(p)R⁷ substituents and/or 1 or 2 (═O) groups, and —C(═O)R⁷,—C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and —SO₂NR⁷R^(7′);

R^(6′) is selected from the group consisting of H, —S(O)_(p)R⁷,—S(O)_(p)NR⁷R^(7′), —C(O)—R¹⁰, —C(O)—OR¹⁰, —C(O)—N(R⁷)R¹⁰ and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one (preferably 1 to 5, more preferably 1 to 3) of halo, —OH,—CN, —NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷ and/or 1 or 2 (═O) groupssubstituents, and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R⁷ and—SO₂NR⁷R^(7′); or

-   -   R⁶ and R^(6′) may be taken together to form (═O);

R⁷ is independently selected from the group consisting of H and alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl,cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted one or more times(preferably 1 to 5, more preferably 1 to 3) by R¹²;

R^(7′) is independently selected from the group consisting of H andalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl,cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted one or more times(preferably 1 to 5, more preferably 1 to 3) by R¹²; or

-   -   a) when a variable is —NR⁷R^(7′), —C(O)NR⁷R^(7′) or        —SO₂NR⁷R^(7′), R⁷ and R^(7′) together with the nitrogen atom to        which they are attached independently form a 3- to 8-membered        heterocyclyl, heterocyclenyl or heteroaryl ring having, in        addition to the N atom, 1 or 2 additional hetero atoms        independently selected from the group consisting of O, N,        —N(R⁹)— and S, wherein said rings are optionally substituted by        1 to 5 independently selected R¹² moieties and/or 1 or 2 (═O)        groups, or    -   b) when a variable is —(CH₂)_(q)ON═CR⁷R^(7′), R⁷ and R^(7′)        together with the carbon atom to which they are attached        independently form a 3- to 8-membered cycloalkyl, cycloalkenyl,        aryl, heterocyclyl, heterocyclenyl or heteroaryl ring, wherein        said heterocyclyl, heterocyclenyl or heteroaryl rings have 1-3        heteroatoms which are independently selected from the group        consisting of O, N, —N(R⁹)— and S, wherein said rings are        optionally substituted by 1 to 5 independently selected R¹²        moieties and/or 1 or 2 (═O) groups,

R⁹ is independently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, and —S(O)_(p)—R¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of whichis optionally substituted with at least one (preferably 1 to 5, morepreferably 1 to 3) of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹substituents and/or 1 or 2 (═O) groups; and

R¹⁰ is independently selected from the group consisting of H, and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups groups, each of which is optionally substitutedwith at least one (preferably 1 to 5, more preferably 1 to 3) of halo,—OH, —CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹ substituents and/or 1 or 2(═O);

R¹¹ is a moiety independently selected from the group consisting of Hand alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl, each of which is optionallysubstituted by at least one (preferably 1 to 5, more preferably 1 to 3)substituent independently selected from the group consisting of halo,—OH, —CN, —NO₂, —N(R^(11′))₂, and —S(O)_(p)R^(11′) and/or 1 or 2 (═O)groups;

R^(11′) is independently selected from the group consisting of H, alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl;

R¹² is independently selected from the group consisting of H, halo, —OH,—CN, —NO₂, —N(R¹¹)₂, —C(O)—OR¹⁴, —N(R¹⁴)—C(O)—R¹⁴, —N(R¹⁴)—C(O)₂—R¹⁴,—C(O)—N(R¹¹)₂, —N(R¹⁴)—S(O)₂—R¹¹, —S(O)₂—N(R¹¹)₂ and —S(O)_(p)R¹¹ and/or1 or 2 (═O) groups, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl,heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl,heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl,heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy,and heterocyclenylalkoxy groups, each of which in turn is optionallysubstituted by at least once (preferably 1 to 5, more preferably 1 to 3)by a substituent selected from the group consisting of H, alkyl,haloalkyl, halo, —OH, optionally substituted alkoxy, optionallysubstituted aryloxy, optionally substituted cycloalkoxy, optionallysubstituted heteroaryloxy, optionally substituted heterocyclenyloxy,—CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹ and/or 1 or 2 (═O) groups, whereinsaid optionally substituted alkoxy, aryloxy, optionally substitutedcycloalkoxy, optionally substituted heteroaryloxy, and heterocyclenyloxywhen substituted are substituted one or more (preferably 1 to 5, morepreferably 1 to 3) times by R¹¹;

R¹⁴ is independently H, alkyl, or aryl;

R¹⁵ is independently selected from the group consisting of H, —C(O)—R¹⁰,—C(O)—OR¹⁰, —C(O)—N(R⁷)(R^(7′)), and —S(O)_(p)—R¹⁰, SO₂—NR⁷R^(7′) andalkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷ and/or1 or 2 (═O) groups substituents, and —C(═O)R⁷, —C(═O)OR⁷,—C(═O)NR⁷R^(7′), —SO₂R⁷ and —SO₂NR⁷R^(7′);

R¹⁶ is H, alkyl or cycloalkyl;

q is independently an integer from 0-10;

n is independently an integer from 0-2;

p is independently an integer from 0-2; and

w is an integer from 0-3.

The compounds of Formulae I and II can be useful as α2C adrenergicreceptor modulators and can be useful in the treatment or prevention ofone or more conditions associated with the α2C receptor by administeringat least one compound of Formula I or Formula II to a mammal in need ofsuch treatment. Conditions that my be treated by modulating the α2Creceptor include allergic rhinitis, congestion (including congestionassociated with perennial allergic rhinitis, seasonal allergic rhinitis,non-allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa,sinusitis, acute rhinosinusitis, or chronic rhinosinusitis, congestioncaused by polyps, or caused by the common cold), pain (e.g., neuropathy,inflammation, arthritis, or diabetes), diarrhea, glaucoma, congestiveheart failure, chronic heart failure, cardiac ischemia, manic disorders,depression, anxiety, migraine, stress-induced urinary incontinence,neuronal damage from ischemia, schizophrenia, attention deficithyperactivity disorder, symptoms of diabetes, post traumatic stressdisorder, Parkinson's disease or a dementia (e.g., Alzheimer's disease).

Another embodiment of this invention is the treatment or prevention ofone or more conditions associated with the α2C receptor by administeringat least one compound of Formula I or Formula II to a mammal in need ofsuch treatment by selectively modulating α2C adrenergic receptors in themammal.

Another embodiment of this invention is the treatment or prevention ofone or more conditions associated with the α2C receptor by administeringan effective amount at least one compound of Formula I or Formula II toa mammal in need of such treatment without modifying blood pressure atthe therapeutic dose.

Another embodiment of the present invention is a method for selectivelymodulating α2C adrenergic receptors in a cell in a mammal in needthereof, comprising contacting said cell with a therapeuticallyeffective amount of at least one compound of Formula I or Formula II ora pharmaceutically acceptable salt, ester, prodrug or salt thereof.

Another embodiment of the present invention is a method for thetreatment of congestion in a mammal in need thereof without modifyingthe blood pressure at therapeutic doses which comprises administering tothe mammal an effective dose of at least one compound having adrenergicactivity wherein said compound is a selective agonist of the α2Creceptor.

DETAILED DESCRIPTION

In an embodiment, the present invention discloses certainspiroaminooxazoline derivatives, which are represented by structuralFormula I, or a pharmaceutically acceptable salt thereof, wherein thevarious moieties are as described above.

In another embodiment, J¹, J² and J³ are each —C(R²)—.

In another embodiment, J², J³ and J⁴ are each —CH—.

In another embodiment, J¹ and J³ are —CH— and J¹ is —N—.

In another embodiment, J² and J³ are —CH— and J² is —N—.

In another embodiment, J¹, J² and J³ are independently —CR²— or —N—.

In another embodiment, J¹ and J² are —CH— and J³ is —N—.

In another embodiment, J¹ and J² are —CH— and J³ is —N—.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, n is 0.

In another embodiment, q is 0 or 1

In another embodiment, p is 1 or 2.

In another embodiment, X is —CH₂—.

In another embodiment, X is —NH—.

In another embodiment, X is —O—.

In another embodiment, X is —S—.

In another embodiment, X is —N(R^(6′)).

In one embodiment R¹ is optionally substituted (preferably 1 to 5 times)aryl (preferably optionally substituted phenyl) or optionallysubstituted (preferably 1 to 5 times) heteroaryl, wherein the optionalsubstituents are, for example, any of the “ring system substituents”identified below. Examples of heteroaryl rings include pyridine,pyrimidine, furan, pyrrole, thiophene, pyridazine, pyrazine, indolizine,oxazole, pyrazole, isoxazole, indole, isoindole, imidazole, indoline,benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole,quinoline, isoquinoline, cinnoline, phthalazine, quinazoline,quinoxaline, and naphthyridine. Preferred heteroaryl rings includepyridine, pyrimidine, furan, pyrrole, thiophene, pyridazine, pyrazine,indole, indoline, benzofuran, benzothiophene, benzimidazole, andbenzthiazole. More preferred heteroaryl rings include pyridine,pyrimidine, pyrazole, isoxazole, and oxazole. Preferred optionalsubstituents include alkyl, haloalkyl, nitro, cyano, halo, hydroxyl,alkoxy, amino, alkylamino, dialkylamino, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 5, preferably 1 to 3, times by alkyl, haloalkyl, nitro, cyano,halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and haloalkoxy.

In another embodiment R¹ is an optionally substituted (preferably 1 to 5times) cycloalkyl or cycloalkenyl ring. Examples of rings includecyclopentane, cyclohexane and cyclohexene. Examples of substituentsinclude any of the “ring system substituents” identified below.Preferred optional substituents include alkyl, haloalkyl, nitro, cyano,halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, haloalkoxy,aryl, and heteroaryl, wherein said aryl and heteroaryl are optionallysubstituted 1 to 5, preferably 1 to 3, times by alkyl, haloalkyl, nitro,cyano, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino andhaloalkoxy.

In another embodiment R¹ is an optionally substituted (preferably 1 to 5times) heterocyclyl or heterocyclenyl ring or cycloalkenyl ring.Examples of rings include morpholine, piperazine, 2-pyrrolidine andtetrahydrofurane. Examples of substituents include any of the “ringsystem substituents” identified below. Preferred optional substituentsinclude Preferred optional substituents include alkyl, haloalkyl, nitro,cyano, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino,haloalkoxy, aryl, and heteroaryl, wherein said aryl and heteroaryl areoptionally substituted 1 to 5, preferably 1 to 3, times by alkyl,haloalkyl, nitro, cyano, halo, hydroxyl, alkoxy, amino, alkylamino,dialkylamino and haloalkoxy.

In another embodiment, R¹ is an optionally substituted pyridine ring.

In another embodiment, R¹ is an optionally substituted pyrimidine ring.

In another embodiment, R¹ is an optionally substituted oxazole ring.

In another embodiment, R¹ is an optionally substituted phenyl ring.

In another embodiment, R¹ is an optionally substituted naphthylene ring.

In another embodiment, R¹ is an optionally substituted isoxazole ring.

In another embodiment, R¹ is an optionally substituted pyrazole ring.

In another embodiment, R¹ is bonded to J¹; J², J³ and J⁴ are —CH—; and Xis —CH₂—.

In another embodiment, R¹ is bonded to J¹; J², J³ and J⁴ are —CH—; and Xis —NH—.

In another embodiment, R¹ is bonded to J¹; J², J³ and J⁴ are —CH—; and Xis —O—.

In another embodiment, R¹ is bonded to J¹; J², J³ and J⁴ are —CH—; and Xis —S—.

In another embodiment, R¹ is bonded to J⁴; J¹, J² and J³ are —CH—; and Xis —CH₂—.

In another embodiment, R¹ is bonded to J⁴; J¹, J² and J³ are —CH—; and Xis —NH—.

In another embodiment, R¹ is bonded to J⁴; J¹, J² and J³ are —CH—; and Xis —O—.

In another embodiment, R¹ is bonded to J⁴; J¹, J² and J³ are —CH—; and Xis —S—.

In another embodiment, R¹ is bonded to J²; J¹, J³ and J⁴ are —CH—; and Xis —CH₂—.

In another embodiment, R¹ is bonded to J²; J¹, J³ and J⁴ are —CH—; and Xis —NH—.

In another embodiment, R¹ is bonded to J²; J¹, J³ and J⁴ are —CH—; and Xis —O—.

In another embodiment, R¹ is bonded to J³; J¹, J² and J⁴ are —CH—; and Xis —CH₂—.

In another embodiment, R¹ is bonded to J³; J¹, J² and J⁴ are —CH—; and Xis —NH—.

In another embodiment, R¹ is bonded to J³; J¹, J² and J⁴ are —CH—; and Xis —O—.

In another embodiment, R¹ is bonded to J³; J¹, J² and J⁴ are —CH—; and Xis —S—.

In another embodiment, Z is —NR⁷R^(7′), wherein R⁷ and R^(7′) areindependently H, alkyl, R¹²-aryl, and R¹²-cycloalkyl.

In another embodiment R⁴ is H, —OH, halo, —CN, —NO₂, —NR⁷R^(7′), whereinR⁷ and R^(7′) are independently H, alkyl, R¹²-aryl, and R¹²-cycloalkyl,alkyl, or haloalkyl

In another embodiment, m is 1 and W is —O—.

In another embodiment, m is 1 and W is —S—.

In another embodiment, the spiro ring is:

In another embodiment, the spiro ring is:

In another embodiment R¹⁵ is H, optionally substituted alkyl, optionallysubstituted cycloalkyl (e.g., cyclopropyl, cyclopentyl, or cyclohexyl)or, optionally substituted aryl (e.g., phenyl), wherein the optionalsubstituents are halo, hydroxyl, amino, alkyl amino, dialkyl amino,nitro, or cyano.

In another embodiment Z is amino, alkyl amino or dialkyl amino.

In another embodiment R¹⁵ is H or alkyl.

In another embodiment, the present invention discloses compounds whichare represented by structural formulae III-VI or a pharmaceuticallyacceptable salt, solvate or ester thereof, wherein the variousdefinitions are those described above for Formula I:

An embodiment of Formulae II-VI is those compounds wherein:

R¹ is optionally substituted aryl, optionally substituted arylalkyl,optionally substituted arylalkoxy, optionally substituted pyridyl,optionally substituted pyrimidyl, optionally substituted furanyl,optionally substituted thiophenyl, optionally substituted quinolinyl,optionally substituted indolyl, optionally substituted pyrrolyl, andoptionally substituted pyrrolidinyl, optionally substituted pyrazolyl,optionally substituted oxazolyl, optionally substituted isoxazolyl,optionally substituted imidazole, optionally substituted pyridazinyl,optionally substituted pyrazinyl, optionally substituted tetrazolyl,optionally substituted imidazopyrimidinyl, optionally substitutedthiazolyl, optionally substituted isothiazolyl, optionally substitutedindazolyl, optionally substituted benzofuranyl, optionally substitutedbenzothiophenyl, optionally substituted isoquinolyl, optionallysubstituted benzimidazolyl, optionally substituted benzthiazolyl,optionally substituted quinoxalinyl, wherein said groups may beoptionally substituted 1 to 3 times with substitutents selected from thegroup consisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl,amino, alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy; and

R¹⁵ is absent or is H or alkyl (e.g., methyl or ethyl)

or a pharmaceutically acceptable salt thereof.

Another embodiment of the compounds of Formula I is compounds of theformula

or a pharmaceutically acceptable salt thereof, wherein the definitionsare the same as those for Formula I.

An embodiment of compounds of Formula VII is those compounds wherein:

R¹ is optionally substituted aryl, optionally substituted pyridyl,optionally substituted pyrimidyl, optionally substituted furanyl,optionally substituted thiophenyl, optionally substituted quinolinyl,optionally substituted indolyl, optionally substituted pyrrolyl, andoptionally substituted pyrrolidinyl, optionally substituted pyrazolyl,optionally substituted oxazolyl, optionally substituted isoxazolyl,optionally substituted imidazole, optionally substituted pyridazinyl,optionally substituted pyrazinyl, optionally substituted tetrazolyl,optionally substituted imidazopyrimidinyl, optionally substitutedthiazolyl, optionally substituted isothiazolyl, optionally substitutedindazolyl, optionally substituted benzofuranyl, optionally substitutedbenzothiophenyl, optionally substituted isoquinolyl, optionallysubstituted benzimidazolyl, optionally substituted benzthiazolyl,optionally substituted quinoxalinyl, wherein said groups may beoptionally substituted 1 to 3 times with substitutents selected from thegroup consisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl,amino, alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R² is H, alkyl, alkenyl, halo, alkoxy, optionally substituted aryl,optionally substituted pyridyl, optionally substituted pyrimidyl,optionally substituted furanyl, optionally substituted thiophenyl,optionally substituted quinolinyl, optionally substituted indolyl,optionally substituted pyrrolyl, and optionally substitutedpyrrolidinyl, optionally substituted pyrazolyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedimidazole, optionally substituted pyridazinyl, optionally substitutedpyrazinyl, optionally substituted tetrazolyl, optionally substitutedimidazopyrimidinyl, optionally substituted thiazolyl, optionallysubstituted isothiazolyl, optionally substituted indazolyl, optionallysubstituted benzofuranyl, optionally substituted benzothiophenyl,optionally substituted isoquinolyl, optionally substitutedbenzimidazolyl, optionally substituted benzthiazolyl, optionallysubstituted quinoxalinyl, wherein said groups may be optionallysubstituted 1 to 3 times with substitutents selected from the groupconsisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)-Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R³ is independently H, alkyl, —OH, halo, or (═O);

R⁴ is H, D, alkyl or deuterated alkyl (e.g., —CH₂D, CHD₂ or CD₃);

R^(4′) is H, D, alkyl or deuterated alkyl (e.g., —CH₂D, CHD₂ or CD₃);and

w is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

Another embodiment of the compounds of Formula I is the compounds of theformula

or a pharmaceutically acceptable salt thereof, wherein the definitionsare the same as those for Formula I.

An embodiment of compounds of Formula VIII is those compounds wherein:

R¹ is optionally substituted aryl, optionally substituted pyridyl,optionally substituted pyrimidyl, optionally substituted furanyl,optionally substituted thiophenyl, optionally substituted quinolinyl,optionally substituted indolyl, optionally substituted pyrrolyl, andoptionally substituted pyrrolidinyl, optionally substituted pyrazolyl,optionally substituted oxazolyl, optionally substituted isoxazolyl,optionally substituted imidazole, optionally substituted pyridazinyl,optionally substituted pyrazinyl, optionally substituted tetrazolyl,optionally substituted imidazopyrimidinyl, optionally substitutedthiazolyl, optionally substituted isothiazolyl, optionally substitutedindazolyl, optionally substituted benzofuranyl, optionally substitutedbenzothiophenyl, optionally substituted isoquinolyl, optionallysubstituted benzimidazolyl, optionally substituted benzthiazolyl,optionally substituted quinoxalinyl, wherein said groups may beoptionally substituted 1 to 3 times with substitutents selected from thegroup consisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl,amino, alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R² is H, alkyl, alkenyl, halo, alkoxy, optionally substituted aryl,optionally substituted pyridyl, optionally substituted pyrimidyl,optionally substituted furanyl, optionally substituted thiophenyl,optionally substituted quinolinyl, optionally substituted indolyl,optionally substituted pyrrolyl, and optionally substitutedpyrrolidinyl, optionally substituted pyrazolyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedimidazole, optionally substituted pyridazinyl, optionally substitutedpyrazinyl, optionally substituted tetrazolyl, optionally substitutedimidazopyrimidinyl, optionally substituted thiazolyl, optionallysubstituted isothiazolyl, optionally substituted indazolyl, optionallysubstituted benzofuranyl, optionally substituted benzothiophenyl,optionally substituted isoquinolyl, optionally substitutedbenzimidazolyl, optionally substituted benzthiazolyl, optionallysubstituted quinoxalinyl, wherein said groups may be optionallysubstituted 1 to 3 times with substitutents selected from the groupconsisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)-Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R³ is independently H, alkyl, —OH, halo, or (═O);

R⁴ is H, D, alkyl or deuterated alkyl (e.g., —CH₂D, CHD₂ or CD₃);

R^(4′) is H, D, alkyl or deuterated alkyl (e.g., —CH₂D, CHD₂ or CD₃);and

w is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

Another embodiment of the compounds of Formula I is compounds of theformula

or a pharmaceutically acceptable salt thereof, wherein the definitionsare the same as those for Formula I.

Another embodiment of the compounds of Formula IX is the compoundswherein

R¹ is optionally substituted aryl, optionally substituted pyridyl,optionally substituted pyrimidyl, optionally substituted furanyl,optionally substituted thiophenyl, optionally substituted quinolinyl,optionally substituted indolyl, optionally substituted pyrrolyl, andoptionally substituted pyrrolidinyl, optionally substituted pyrazolyl,optionally substituted oxazolyl, optionally substituted isoxazolyl,optionally substituted imidazole, optionally substituted pyridazinyl,optionally substituted pyrazinyl, optionally substituted tetrazolyl,optionally substituted imidazopyrimidinyl, optionally substitutedthiazolyl, optionally substituted isothiazolyl, optionally substitutedindazolyl, optionally substituted benzofuranyl, optionally substitutedbenzothiophenyl, optionally substituted isoquinolyl, optionallysubstituted benzimidazolyl, optionally substituted benzthiazolyl,optionally substituted quinoxalinyl, wherein said groups may beoptionally substituted 1 to 3 times with substitutents selected from thegroup consisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl,amino, alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R² is H, alkyl, alkenyl, halo, alkoxy, optionally substituted aryl,optionally substituted pyridyl, optionally substituted pyrimidyl,optionally substituted furanyl, optionally substituted thiophenyl,optionally substituted quinolinyl, optionally substituted indolyl,optionally substituted pyrrolyl, and optionally substitutedpyrrolidinyl, optionally substituted pyrazolyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedimidazole, optionally substituted pyridazinyl, optionally substitutedpyrazinyl, optionally substituted tetrazolyl, optionally substitutedimidazopyrimidinyl, optionally substituted thiazolyl, optionallysubstituted isothiazolyl, optionally substituted indazolyl, optionallysubstituted benzofuranyl, optionally substituted benzothiophenyl,optionally substituted isoquinolyl, optionally substitutedbenzimidazolyl, optionally substituted benzthiazolyl, optionallysubstituted quinoxalinyl, wherein said groups may be optionallysubstituted 1 to 3 times with substitutents selected from the groupconsisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)-Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R³ is independently H, alkyl, —OH, halo, or (═O);

R⁴ is H, D, alkyl or deuterated alkyl (e.g., —CH₂D, CHD₂ or CD₃);

R^(4′) is H, D, alkyl or deuterated alkyl (e.g., —CH₂D, CHD₂ or CD₃);

Z is H, alkyl or NH₂;

R¹⁵ is H or alkyl (e.g., methyl, ethyl, propyl etc.); and

w is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

Another embodiment of the compounds of Formula I is the compounds of theformula

or a pharmaceutically acceptable salt thereof, wherein the definitionsare the same as those for Formula I.

An embodiment of the compounds of Formula X is those compounds wherein

R¹ is optionally substituted aryl, optionally substituted pyridyl,optionally substituted pyrimidyl, optionally substituted furanyl,optionally substituted thiophenyl, optionally substituted quinolinyl,optionally substituted indolyl, optionally substituted pyrrolyl, andoptionally substituted pyrrolidinyl, optionally substituted pyrazolyl,optionally substituted oxazolyl, optionally substituted isoxazolyl,optionally substituted imidazole, optionally substituted pyridazinyl,optionally substituted pyrazinyl, optionally substituted tetrazolyl,optionally substituted imidazopyrimidinyl, optionally substitutedthiazolyl, optionally substituted isothiazolyl, optionally substitutedindazolyl, optionally substituted benzofuranyl, optionally substitutedbenzothiophenyl, optionally substituted isoquinolyl, optionallysubstituted benzimidazolyl, optionally substituted benzthiazolyl,optionally substituted quinoxalinyl, wherein said groups may beoptionally substituted 1 to 3 times with substitutents selected from thegroup consisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl,amino, alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R² is H, alkyl, alkenyl, halo, alkoxy, optionally substituted aryl,optionally substituted pyridyl, optionally substituted pyrimidyl,optionally substituted furanyl, optionally substituted thiophenyl,optionally substituted quinolinyl, optionally substituted indolyl,optionally substituted pyrrolyl, and optionally substitutedpyrrolidinyl, optionally substituted pyrazolyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedimidazole, optionally substituted pyridazinyl, optionally substitutedpyrazinyl, optionally substituted tetrazolyl, optionally substitutedimidazopyrimidinyl, optionally substituted thiazolyl, optionallysubstituted isothiazolyl, optionally substituted indazolyl, optionallysubstituted benzofuranyl, optionally substituted benzothiophenyl,optionally substituted isoquinolyl, optionally substitutedbenzimidazolyl, optionally substituted benzthiazolyl, optionallysubstituted quinoxalinyl, wherein said groups may be optionallysubstituted 1 to 3 times with substitutents selected from the groupconsisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)-Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R³ is independently H, alkyl, —OH, halo, or (═O); and

w is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

Another embodiment of the compounds of Formula I is the compounds of theformula

or a pharmaceutically acceptable salt thereof, wherein the definitionsare the same as those for Formula I.

Another embodiment of compounds of Formula XI is the compounds wherein:

R¹ is optionally substituted aryl, optionally substituted pyridyl,optionally substituted pyrimidyl, optionally substituted furanyl,optionally substituted thiophenyl, optionally substituted quinolinyl,optionally substituted indolyl, optionally substituted pyrrolyl, andoptionally substituted pyrrolidinyl, optionally substituted pyrazolyl,optionally substituted oxazolyl, optionally substituted isoxazolyl,optionally substituted imidazole, optionally substituted pyridazinyl,optionally substituted pyrazinyl, optionally substituted tetrazolyl,optionally substituted imidazopyrimidinyl, optionally substitutedthiazolyl, optionally substituted isothiazolyl, optionally substitutedindazolyl, optionally substituted benzofuranyl, optionally substitutedbenzothiophenyl, optionally substituted isoquinolyl, optionallysubstituted benzimidazolyl, optionally substituted benzthiazolyl,optionally substituted quinoxalinyl, wherein said groups may beoptionally substituted 1 to 3 times with substitutents selected from thegroup consisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl,amino, alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R² is H, alkyl, alkenyl, halo, alkoxy, optionally substituted aryl,optionally substituted pyridyl, optionally substituted pyrimidyl,optionally substituted furanyl, optionally substituted thiophenyl,optionally substituted quinolinyl, optionally substituted indolyl,optionally substituted pyrrolyl, and optionally substitutedpyrrolidinyl, optionally substituted pyrazolyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedimidazole, optionally substituted pyridazinyl, optionally substitutedpyrazinyl, optionally substituted tetrazolyl, optionally substitutedimidazopyrimidinyl, optionally substituted thiazolyl, optionallysubstituted isothiazolyl, optionally substituted indazolyl, optionallysubstituted benzofuranyl, optionally substituted benzothiophenyl,optionally substituted isoquinolyl, optionally substitutedbenzimidazolyl, optionally substituted benzthiazolyl, optionallysubstituted quinoxalinyl, wherein said groups may be optionallysubstituted 1 to 3 times with substitutents selected from the groupconsisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)-Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R³ is independently H, alkyl, —OH, halo, or (═O);

R⁴ and R^(4′) are independently H or alkyl; and

w is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

A group of compounds falling within Formula I are those shown below:

Another group of compounds falling within Formula I are those shownbelow:

Another embodiment the compound of Formula I or a pharmaceuticallyacceptable salt thereof is present in its isolated and purified form.

In an another embodiment, the present invention discloses certainspiroaminooxazoline derivatives, which are represented by structuralFormula II, or a pharmaceutically acceptable salt thereof, wherein thevarious moieties are as described above.

In another embodiment of Formula II, J¹, J² and J³ are each —C(R²)—.

In another embodiment of Formula II, J², J³ and J⁴ are each —CH—.

In another embodiment of Formula II, J¹ and J³ are —CH— and J¹ is —N—.

In another embodiment of Formula II, J² and J³ are —CH— and J² is —N—.

In another embodiment, J¹, J² and J³ are independently —CR²— or —N—.

In another embodiment of Formula II, J¹ and J² are —CH— and J³ is —N—.

In another embodiment of Formula II, J¹ and J² are —CH— and J³ is —N—.

In another embodiment of Formula II, n is 1.

In another embodiment of Formula II, n is 2.

In another embodiment of Formula II, n is 0.

In another embodiment of Formula II, q is 0 or 1

In another embodiment of Formula II, p is 1 or 2.

In another embodiment of Formula II, X is —CH₂—.

In another embodiment of Formula II, X is —NH—.

In another embodiment of Formula II, X is —O—.

In another embodiment of Formula II, X is —S—.

In another embodiment of Formula II, X is —N(R^(6′)).

In one embodiment of Formula II, R¹ is optionally substituted(preferably 1 to 5 times) aryl (preferably optionally substitutedphenyl) or optionally substituted (preferably 1 to 5 times) heteroaryl,wherein the optional substituents are, for example, any of the “ringsystem substituents” identified below. Examples of heteroaryl ringsinclude pyridine, pyrimidine, furan, pyrrole, thiophene, pyridazine,pyrazine, indolizine, oxazole, pyrazole, isoxazole, indole, isoindole,imidazole, indoline, benzofuran, benzothiophene, indazole,benzimidazole, benzthiazole, quinoline, isoquinoline, cinnoline,phthalazine, quinazoline, quinoxaline, and naphthyridine. Preferredheteroaryl rings include pyridine, pyrimidine, furan, pyrrole,thiophene, pyridazine, pyrazine, indole, indoline, benzofuran,benzothiophene, benzimidazole, and benzthiazole. More preferredheteroaryl rings include pyridine, pyrimidine, pyrazole, isoxazole, andoxazole. Preferred optional substituents include alkyl, haloalkyl,nitro, cyano, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino,haloalkoxy, aryl, and heteroaryl, wherein said aryl and heteroaryl areoptionally substituted 1 to 5, preferably 1 to 3, times by alkyl,haloalkyl, nitro, cyano, halo, hydroxyl, alkoxy, amino, alkylamino,dialkylamino and haloalkoxy.

In another embodiment of Formula II, R¹ is an optionally substituted(preferably 1 to 5 times) cycloalkyl or cycloalkenyl ring. Examples ofrings include cyclopentane, cyclohexane and cyclohexene. Examples ofsubstituents include any of the “ring system substituents” identifiedbelow. Preferred optional substituents include alkyl, haloalkyl, nitro,cyano, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino,haloalkoxy, aryl, and heteroaryl, wherein said aryl and heteroaryl areoptionally substituted 1 to 5, preferably 1 to 3, times by alkyl,haloalkyl, nitro, cyano, halo, hydroxyl, alkoxy, amino, alkylamino,dialkylamino and haloalkoxy.

In another embodiment of Formula II, R¹ is an optionally substituted(preferably 1 to 5 times) heterocyclyl or heterocyclenyl ring orcycloalkenyl ring. Examples of rings include morpholine, piperazine,2-pyrrolidine and tetrahydrofurane. Examples of substituents include anyof the “ring system substituents” identified below. Preferred optionalsubstituents include Preferred optional substituents include alkyl,haloalkyl, nitro, cyano, halo, hydroxyl, alkoxy, amino, alkylamino,dialkylamino, haloalkoxy, aryl, and heteroaryl, wherein said aryl andheteroaryl are optionally substituted 1 to 5, preferably 1 to 3, timesby alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, alkoxy, amino,alkylamino, dialkylamino and haloalkoxy.

In another embodiment of Formula II, R¹ is an optionally substitutedpyridine ring.

In another embodiment of Formula II, R¹ is an optionally substitutedpyrimidine ring.

In another embodiment of Formula II, R¹ is an optionally substitutedoxazole ring.

In another embodiment of Formula II, R¹ is an optionally substitutedphenyl ring.

In another embodiment of Formula II, R¹ is an optionally substitutednaphthylene ring.

In another embodiment of Formula II, R¹ is an optionally substitutedisoxazole ring.

In another embodiment of Formula II, R¹ is an optionally substitutedpyrazole ring.

In another embodiment of Formula II, R¹ is bonded to J¹; J², J³ and J⁴are —CH—; and X is —CH₂—.

In another embodiment of Formula II, R¹ is bonded to J¹; J², J³ and J⁴are —CH—; and X is —NH—.

In another embodiment of Formula II, R¹ is bonded to J¹; J², J³ and J⁴are —CH—;

and X is —O—.

In another embodiment of Formula II, R¹ is bonded to J¹; J², J³ and J⁴are —CH—; and X is —S—.

In another embodiment of Formula II, R¹ is bonded to J⁴; J¹, J² and J³are —CH—;

and X is —CH₂—.

In another embodiment of Formula II, R¹ is bonded to J⁴; J¹, J² and J³are —CH—;

and X is —NH—.

In another embodiment of Formula II, R¹ is bonded to J⁴; J¹, J² and J³are —CH—; and X is —O—.

In another embodiment of Formula II, R¹ is bonded to J⁴; J¹, J² and J³are —CH—;

and X is —S—.

In another embodiment of Formula II, R¹ is bonded to J²; J¹, J³ and J⁴are —CH—; and X is —CH₂—.

In another embodiment of Formula II, R¹ is bonded to J²; J¹, J³ and J⁴are —CH—; and X is —NH—.

In another embodiment of Formula II, R¹ is bonded to J²; J¹, J³ and J⁴are —CH—; and X is —O—.

In another embodiment of Formula II, R¹ is bonded to J²; J¹, J³ and J⁴are —CH—; and X is —S—.

In another embodiment of Formula II, R¹ is bonded to J³; J¹, J² and J⁴are —CH—; and X is —CH₂—.

In another embodiment of Formula II, R¹ is bonded to J³; J¹, J² and J⁴are —CH—; and X is —NH—.

In another embodiment of Formula II, R¹ is bonded to J³; J¹, J² and J⁴are —CH—; and X is —O—.

In another embodiment of Formula II, R¹ is bonded to J³; J¹, J² and J⁴are —CH—; and X is —S—.

In another embodiment R⁴ is H, D, —OH, halo, —CN, —NO₂, alkyl,deuterated alkyl (e.g., CD₃) or —NR⁷R^(7′), wherein R⁷ and R^(7′) areindependently H, alkyl, R¹²-aryl, and R¹²-cycloalkyl, alkyl, orhaloalkyl.

In another embodiment of Formula II, R¹⁶ is H or alkyl.

In another embodiment of Formula II, R^(4′) is H or D.

Another embodiment of the compounds of Formula II is compounds of theformula

or a pharmaceutically acceptable salt thereof, wherein the definitionsare the same as those for Formula II.

Another embodiment of the compounds of Formula XII is the compoundswherein

R¹ is optionally substituted aryl, optionally substituted pyridyl,optionally substituted pyrimidyl, optionally substituted furanyl,optionally substituted thiophenyl, optionally substituted quinolinyl,optionally substituted indolyl, optionally substituted pyrrolyl, andoptionally substituted pyrrolidinyl, optionally substituted pyrazolyl,optionally substituted oxazolyl, optionally substituted isoxazolyl,optionally substituted imidazole, optionally substituted pyridazinyl,optionally substituted pyrazinyl, optionally substituted tetrazolyl,optionally substituted imidazopyrimidinyl, optionally substitutedthiazolyl, optionally substituted isothiazolyl, optionally substitutedindazolyl, optionally substituted benzofuranyl, optionally substitutedbenzothiophenyl, optionally substituted isoquinolyl, optionallysubstituted benzimidazolyl, optionally substituted benzthiazolyl,optionally substituted quinoxalinyl, wherein said groups may beoptionally substituted 1 to 3 times with substitutents selected from thegroup consisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl,amino, alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R² is H, alkyl, alkenyl, halo, alkoxy, optionally substituted aryl,optionally substituted pyridyl, optionally substituted pyrimidyl,optionally substituted furanyl, optionally substituted thiophenyl,optionally substituted quinolinyl, optionally substituted indolyl,optionally substituted pyrrolyl, and optionally substitutedpyrrolidinyl, optionally substituted pyrazolyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedimidazole, optionally substituted pyridazinyl, optionally substitutedpyrazinyl, optionally substituted tetrazolyl, optionally substitutedimidazopyrimidinyl, optionally substituted thiazolyl, optionallysubstituted isothiazolyl, optionally substituted indazolyl, optionallysubstituted benzofuranyl, optionally substituted benzothiophenyl,optionally substituted isoquinolyl, optionally substitutedbenzimidazolyl, optionally substituted benzthiazolyl, optionallysubstituted quinoxalinyl, wherein said groups may be optionallysubstituted 1 to 3 times with substitutents selected from the groupconsisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)-Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R³ is independently H, alkyl, —OH, halo, or (═O);

R⁴ is H, D, alkyl or deuterated alkyl (e.g., —CH₂D, CHD₂ or CD₃);

R^(4′) is H, D, alkyl or deuterated alkyl (e.g., —CH₂D, CHD₂ or CD₃);and

R¹⁵ is H or alkyl (e.g., methyl, ethyl, propyl etc.); and

w is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

Another embodiment of the compounds of Formula II is compounds of theformula

or a pharmaceutically acceptable salt thereof, wherein the definitionsare the same as those for Formula II.

Another embodiment of the compounds of Formula XIII is the compoundswherein

R¹ is optionally substituted aryl, optionally substituted pyridyl,optionally substituted pyrimidyl, optionally substituted furanyl,optionally substituted thiophenyl, optionally substituted quinolinyl,optionally substituted indolyl, optionally substituted pyrrolyl, andoptionally substituted pyrrolidinyl, optionally substituted pyrazolyl,optionally substituted oxazolyl, optionally substituted isoxazolyl,optionally substituted imidazole, optionally substituted pyridazinyl,optionally substituted pyrazinyl, optionally substituted tetrazolyl,optionally substituted imidazopyrimidinyl, optionally substitutedthiazolyl, optionally substituted isothiazolyl, optionally substitutedindazolyl, optionally substituted benzofuranyl, optionally substitutedbenzothiophenyl, optionally substituted isoquinolyl, optionallysubstituted benzimidazolyl, optionally substituted benzthiazolyl,optionally substituted quinoxalinyl, wherein said groups may beoptionally substituted 1 to 3 times with substitutents selected from thegroup consisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl,amino, alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R² is H, alkyl, alkenyl, halo, alkoxy, optionally substituted aryl,optionally substituted pyridyl, optionally substituted pyrimidyl,optionally substituted furanyl, optionally substituted thiophenyl,optionally substituted quinolinyl, optionally substituted indolyl,optionally substituted pyrrolyl, and optionally substitutedpyrrolidinyl, optionally substituted pyrazolyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedimidazole, optionally substituted pyridazinyl, optionally substitutedpyrazinyl, optionally substituted tetrazolyl, optionally substitutedimidazopyrimidinyl, optionally substituted thiazolyl, optionallysubstituted isothiazolyl, optionally substituted indazolyl, optionallysubstituted benzofuranyl, optionally substituted benzothiophenyl,optionally substituted isoquinolyl, optionally substitutedbenzimidazolyl, optionally substituted benzthiazolyl, optionallysubstituted quinoxalinyl, wherein said groups may be optionallysubstituted 1 to 3 times with substitutents selected from the groupconsisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)-Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy;

R³ is independently H, alkyl, —OH, halo, or (═O);

R⁴ is H, D, alkyl or deuterated alkyl (e.g., —CH₂D, CHD₂ or CD₃);

R^(4′) is H, D, alkyl or deuterated alkyl (e.g., —CH2D, CHD2 or CD3);and

R¹⁵ is H or alkyl (e.g., methyl, ethyl, propyl etc.); and

w is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.

Two compound falling within Formula II is a compound of the formula

and its stereoisomer:

In another embodiment the compound of Formula II or a pharmaceuticallyaccept salt thereof is present in its isolated and purified form.

One embodiment of the present invention is compounds that act asagonists of the α2C receptor. Alpha-2C receptor agonists can by used inthe treatment or prevention of allergic rhinitis, congestion (including,but not limited to nasal congestion), migraine, congestive heartfailure, chronic heart failure, cardiac ischemia, glaucoma,stress-induced urinary incontinence, attention deficit hyperactivitydisorder, neuronal damage from ischemia and psychotic disorders.Further, alpha-2C receptor agonists can be useful in the treatment ofpain (both chronic and acute), such as pain that is caused byinflammation, neuropathy, arthritis (including osteo and rheumatoidarthritis), diabetes (e.g., diabetes mellitus or diabetes insipidus) orpain of an unknown origin. Examples of neuropathic pain may include butnot limited to; diabetic neuropathy, neuralgia of any etiology (e.g.post-herpetic, trigeminal), chemotherapy-induced neuropathy, HIV, lowerback pain of neuropathic origin (e.g. sciatica), traumatic peripheralnerve injury of any etiology, central pain (e.g. post-stroke, thalamic,spinal nerve injury). Other pain that can be treated is nociceptive painand pain that is visceral in origin or pain that is secondary toinflammation or nerve damage in other diseases or diseases of unknownorigin. Further, alpha-2C receptor agonists can be useful in thetreatment of symptoms of diabetes. Examples of symptoms of diabetes mayinclude but are not limited to: hyperglycemia, hypertriglyceridemia,increased levels of blood insulin and hyperlipidemia.

A compound is defined to be an agonist of the alpha-2c receptor if thecompound's efficacy at the α2C receptor is ≧30% E_(max) (GTPγS assay).

A further embodiment of the present invention are that act selectively,and preferably even specifically, as agonists of the α2C or the α2B/α2C(hereinafter referred to as α2C or α2B/2C) receptor subtypes inpreference over the α2A receptor subtype and that act functionallyselectively as agonists of the α2C or the α2B/2C receptor subtype inpreference over the α2A receptor subtype possess desirable therapeuticproperties associated with adrenergic receptors but without having oneor more undesirable side effects such as changes in blood pressure orsedation. For the purposes of the present invention, a compound isdefined to be a specific or at least functionally selective agonist ofthe α2C receptor subtype over the α2A receptor subtype if the compound'sefficacy at the α2C receptor is 30% E_(max) (GTPγS assay) and itsefficacy at the α2A receptor is 35% E_(max), (GTPγS assay).

In another embodiment of the present invention the compound acts as anantagonist of the alpha-2C receptor. Alpha-2C receptor antagonists canbe used in the treatment or prevention of disease states such asdepression, schizophrenia, post tramautic stress disorder, Parkinson'sdisease, dementias (e.g., Alzheimer's disease and neuropathic disorders.

A compound is defined to be an antagonist of the alpha-2C receptor ifthe compounds's efficacy at the α2C receptor is <30% E_(max) (GTPγSassay) and the binding inhibition of at the α2C receptor (K_(i)) is <500nM, preferably <200 nM, and most preferably <20 nM. In a furtherembodiment of the present invention, the α2C receptor subtypeantagonists possess desirable therapeutic properties associated with theα2C adrenergic receptor but without having one or more undesirable sideeffects associated with α2A agonism. For the purposes of this invention,compounds that act as antagonists at the α2C receptor subtype preferablydo not possess an efficacy at the α2A receptor of 35% E_(max) or more(GTPγS assay).

Alternatively, the present invention provides for a method for thetreatment of congestion in a mammal in need thereof which comprisesadministering to a mammal an effective dose of at least one compoundhaving adrenergic activity wherein said compound is a functionallyselective agonist of the α2c receptor or the α2C/αB adrenergic receptor.

A further embodiment of the present invention is a method for thetreatment of congestion in a mammal in need thereof which comprisesadministering to a mammal an effective dose of at least one compoundhaving adrenergic activity wherein said compound is a functionallyselective agonist of the α2C receptor or the α2C/αB adrenergic receptor,wherein the selective agonist of the α2c receptor or the α2C/αBadrenergic receptor has an efficacy that is greater than or equal to 30%E_(max) when assayed in the GTPγS assay and its efficacy at the α2Areceptor is 35% E_(max) (GTPγS assay).

A further embodiment of the present invention is a method for treatingone or more conditions associated with α2C adrenergic receptors,comprising administering to a mammal in need of such treatment acompound of Formulae I or II or a pharmaceutically acceptable saltthereof.

Another embodiment of the present invention is a method for treating oneor more conditions associated with α2C adrenergic receptors, comprisingadministering to a mammal in need of such treatment a compound ofFormulae I or II or a pharmaceutically acceptable salt thereof whereinthe conditions are selected from the group consisting of allergicrhinitis, congestion, pain, diarrhea, glaucoma, congestive heartfailure, chronic heart failure, cardiac ischemia, manic disorders,depression, anxiety, migraine, stress-induced urinary incontinence,neuronal damage from ischemia, schizophrenia, attention deficithyperactivity disorder, and symptoms of diabetes.

Another embodiment of the present invention is a method for treating oneor more conditions associated with α2C adrenergic receptors, comprisingadministering to a mammal in need of such treatment a compound ofFormulae I or II or a pharmaceutically acceptable salt thereof whereinthe condition is congestion.

Another embodiment of the present invention is a method for treating oneor more conditions associated with α2C adrenergic receptors, comprisingadministering to a mammal in need of such treatment a compound ofFormulae I or II or a pharmaceutically acceptable salt thereof whereinthe condition is congestion and the congestion is associated withperennial allergic rhinitis, seasonal allergic rhinitis, non-allergicrhinitis, vasomotor rhinitis, rhinitis medicamentosa, sinusitis, acuterhinosinusitis, or chronic rhinosinusitis or the congestion is caused bypolyps or is associated with the common cold.

Another embodiment of the present invention is a method for treating oneor more conditions associated with α2C adrenergic receptors, comprisingadministering to a mammal in need of such treatment a compound ofFormulae I or II or a pharmaceutically acceptable salt thereof whereinthe condition is pain.

Another embodiment of the present invention is a method for treating oneor more conditions associated with α2C adrenergic receptors, comprisingadministering to a mammal in need of such treatment a compound ofFormulae I or II or a pharmaceutically acceptable salt thereof whereinthe condition is pain wherein the pain is associated with neuropathy,inflammation, arthritis, or diabetis.

Another embodiment of the present invention is a method for treating oneor more conditions associated with α2C adrenergic receptors, comprisingadministering to a mammal in need of such treatment a compound ofFormulae I or II or a pharmaceutically acceptable salt thereof whereinthe condition is Alzheimer's disease, depression, anxiety or Parkinson'sdisease.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“alpha-2C modulator” or “α2C modulator” means that a compound hasaffinity for (or binds to) the α2C receptor which provokes a biologicalresponse (i.e., either an agonistic or antagonistic response).

“alpha-2C receptor agonist or “α2C receptor agonist” is a compound thathas affinity for the α2C receptor and elicits a biological response thatmimics the response observed by the endrogenous ligand (e.g.,neurotransmitter) that binds to the same receptor.

“alpha-2C receptor antagonist or “α2C receptor antagonist” is a compoundthat has affinity for the α2C receptor and elicits a biological responsethat blocks or dampens the response observed by the endrogenous ligand(e.g., neurotransmitter) that binds to the same receptor.

“Congestion” refers to all type of congestion including, but not limitedto, congestion associated with perennial allergic rhinitis, seasonalallergic rhinitis, non-allergic rhinitis, vasomotor rhinitis, rhinitismedicamentosa, sinusitis, acute rhinosinusitis, or chronicrhinosinusitis or when the congestion is caused by polyps or isassociated with the common cold.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.

“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The term “substitutedalkyl” means that the alkyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limitingexamples of suitable alkyl groups include methyl, ethyl, n-propyl,isopropyl and t-butyl.

“Deuterated alkyl” means an alkyl group wherein at least on of thehydrogens in the aliphatic hydrocarbon group is replaced by a deuteriumatom. Examples of deuterated alkyl groups include, for example, —CDH₃,—CD₂H, —CD₃, —CH₂CD₃ etc. This term covers deuterated alkyl groupswherein the amount of deuterium is enriched so that a group containing anaturally occurring amount of deuterium is not contemplated.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl, aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term “substitutedalkynyl” means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of alkyl, aryl andcycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring system, in whichat least one of the multicyclic rings is an aryl ring, comprising about6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.The aryl group can be optionally substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined herein. Non-limiting examples of suitable aryl groups includephenyl and naphthyl. Non-limiting examples of aryl multicyclic ringsystems include:

“Heteroaryl” means an aromatic monocyclic or multicyclic ring system, inwhich at least one of the multicyclic rings is aromatic, comprisingabout 5 to about 14 ring atoms, preferably about 5 to about 10 ringatoms, in which one or more of the ring atoms is an element other thancarbon, for example nitrogen, oxygen or sulfur, alone or in combination.Preferred heteroaryls contain about 5 to about 6 ring atoms. The“heteroaryl” can be optionally substituted by one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before the heteroaryl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively, ispresent as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

Non-limiting examples of heteroaryl multicyclic ring systems include:

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.Non-limiting example of a suitable alkylaryl group is tolyl. The bond tothe parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Halogen” and “Halo” mean fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine or bromine, and more preferred arefluorine and chlorine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— andY₁Y₂NSO₂—, wherein Y₁ and Y₂ may be the same or different and areindependently selected from the group consisting of hydrogen, alkyl,aryl, and aralkyl.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protected moieties are also consideredpart of this invention. The heterocyclyl can be optionally substitutedby one or more “ring system substituents” which may be the same ordifferent, and are as defined herein. The nitrogen or sulfur atom of theheterocyclyl can be optionally oxidized to the corresponding N-oxide,S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclicheterocyclyl rings include piperidyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

Compounds of Formulae I and II and salts, esters, solvates and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention. Non-limiting examples of tautomeric forms thatare part of this invention are as follows:

It should be noted that in saturated heterocyclyl containing systems ofthis invention, there are no hydroxyl, amino, or thiol groups on carbonatoms adjacent to a N, O or S atom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5. It shouldalso be noted that this definition does not preclude (═O), (═S), or (═N)substitutions, or their tautomeric forms, on C atoms adjacent to a N, Oor S. Thus, for example, in the above ring, (═O) substitution on carbon5, or its imino ether tautomer is allowed.

Non-limiting examples which illustrate the present invention are asfollows:

The following non-limiting examples serve to illustrate radicals notcontemplated by the present invention:

“Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Heterocyclylalkyl” means a heterocyclyl-alkyl group in which theheterocyclyl and the alkyl are as previously described. Preferredheterocyclylalkyls contain a lower alkyl group. Non-limiting examples ofsuitable heterocyclylalkyl groups include piperidylmethyl,piperidylethyl, pyrrolidylmethyl, morpholinylpropyl, piperazinylethyl,azindylmethyl, azetidylethyl, oxiranylpropyl and the like. The bond tothe parent moiety is through the alkyl group.

“Heterocyclenyl” (or “heterocycloalkeneyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more ring system substituents,wherein “ring system substituent” is as defined above. The nitrogen orsulfur atom of the heterocyclenyl can be optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples ofsuitable monocyclic azaheterocyclenyl groups include1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl,1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl,3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 2-oxazolinyl,2-thiazolinyl, and the like. Non-limiting examples of suitableoxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl,fluorodihydrofuranyl, and the like. Non-limiting example of a suitablemulticyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.Non-limiting examples of suitable monocyclic thiaheterocyclenyl ringsinclude dihydrothiophenyl, dihydrothiopyranyl, and the like.

“Heterocyclenylalkyl” means a heterocyclenyl-alkyl group in which theheterocyclenyl and the alkyl are as previously described.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an organic acid group in which the —OH of the carboxylgroup is replaced by some other substituent. Suitable non-limitingexamples include H—C(O)—, alkyl-C(O)—, cycloalkyl-C(O)—,heterocyclyl-C(O)—, and heteroaryl-C(O)— groups in which the variousgroups are as previously described. The bond to the parent moiety isthrough the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” or “arylalkyloxy” means an aralkyl-O— group in which thearalkyl group is as previously described. Non-limiting examples ofsuitable aralkyloxy groups include benzyloxy and 1- or2-naphthalenemethoxy. The bond to the parent moiety is through the etheroxygen.

“Heteroarylalkoxy” means a heteroarylalkyl-O-group in which theheteroarylalkyl group is as previously described.

“Heterocyclylalkoxy” means a heterocyclylalkyl-O group in which thehetrocyclylalkyl group is as previously described.

“Heterocyclenylalkoxy” means a heterocyclenylalkyl-O group in which theheterocyclenylalkyl group is as previously described.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

It is noted that carbons of Formulae I and II can be replaced with 1-3silicon atoms, provided all valency requirements are satisfied.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The straight line

as a bond generally indicates a mixture of, or either of, the possibleisomers, non-limiting example(s) include, containing (R)- and(S)-stereochemistry. For example,

means containing both

A dashed line

represents an optional bond.

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring atoms, non-limiting examples include carbon, nitrogenand sulfur ring atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples and Tables herein is assumed to have thehydrogen atom to satisfy the valences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or formula, its definition on eachoccurrence is independent of its definition at every other occurrence.

Unless defined otherwise, all definitions for the variables follow theconvention that the group to the right forms the point of attachment tothe molecule; i.e., if a definition is arylalkyl, this means that thealkyl portion of the definition is attached to the molecule.

Further, all divalent variable are attached from left to right. Forexample when R² is —[C(R^(a))(R^(b))]_(q)N(R⁷)YR^(7′) and Y is —C(═O)—,—C(═O)O— or —C(═O)NR⁷, then R² forms the group—[C(R^(a))(R^(b))]_(q)N(R⁷)—C(═O)—R^(7′),—[C(R^(a))(R^(b))]_(q)N(R⁷)—C(═O)O—R⁷, or—[C(R^(a))(R^(b))]_(q)N(R⁷)—C(═O)N(R⁷)(R^(7′)).

In this application, unless otherwise indicated, whenever there is astructural formula provided, such as those of Formulae I to XIII, thisformula is intended to encompass all forms of a compound such as, forexample, any solvates, hydrates, stereoisomers, tautomers, etc.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of formulae I and II or a salt and/orsolvate thereof. A discussion of prodrugs is provided in T. Higuchi andV. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

For example, if a compound of Formulae I and II or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formulae I and II contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, —P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formulae I and II incorporates —NH— functional group,such as in a primary or secondary amine or in a nitrogen-containingheterocycle, such as imidazole or piperazine ring, a prodrug can beformed by the replacement of a hydrogen atom in the amine group with agroup such as, for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl whereR and R′ are each independently (C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl,benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl,—C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ whereinY² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl, carboxy (C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N- or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵wherein Y⁴ is H or methyl and Y⁵ is mono-N- or di-N,N—(C₁-C₆)alkylaminomorpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of illustrative solvatesinclude ethanolates, methanolates, and the like. “Hydrate” is a solvatewherein the solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

Metabolic conjugates, such as glucuronides and sulfates which canundergo reversible conversion to the compounds of Formulae I and II arecontemplated in the present invention.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in producing the desired therapeutic, ameliorative, inhibitoryor preventative effect.

The terms “purified”, “in purified form” or “in isolated and purifiedform,” as used herein, for a compound refers to the physical state ofsaid compound after being isolated from a synthetic process (e.g. from areaction mixture), or natural source or combination thereof. Thus, theterm “purified”, “in purified form” or “in isolated and purified form”for a compound refers to the physical state of said compound after beingobtained from a purification process or processes described herein orwell known to the skilled artisan (e.g., chromatography,recrystallization and the like), in sufficient purity to becharacterizable by standard analytical techniques described herein orwell known to the skilled artisan.

“Capsule” is meant to describe a special container or enclosure made ofmethyl cellulose, polyvinyl alcohols, or denatured gelatins or starchfor holding or containing compositions comprising the activeingredients. Hard shell capsules are typically made of blends ofrelatively high gel strength bone and pork skin gelatins. The capsuleitself may contain small amounts of dyes, opaquing agents, plasticizersand preservatives.

“Tablet” is meant to describe a compressed or molded solid dosage formcontaining the active ingredients with suitable diluents. The tablet canbe prepared by compression of mixtures or granulations obtained by wetgranulation, dry granulation or by compaction.

“Oral gels” is meant to describe to the active ingredients dispersed orsolubilized in a hydrophillic semi-solid matrix.

“Powders for constitution” refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

“Diluent” refers to substances that usually make up the major portion ofthe composition or dosage form. Suitable diluents include sugars such aslactose, sucrose, mannitol and sorbitol; starches derived from wheat,corn, rice and potato; and celluloses such as microcrystallinecellulose. The amount of diluent in the composition can range from about10 to about 90% by weight of the total composition, preferably fromabout 25 to about 75%, more preferably from about 30 to about 60% byweight, even more preferably from about 12 to about 60%.

“Disintegrants” refers to materials added to the composition to help itbreak apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches; “cold water soluble” modified starchessuch as sodium carboxymethyl starch; natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar; cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose;microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose; alginates such as alginic acid and sodiumalginate; clays such as bentonites; and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 15% by weight of the composition, more preferably from about 4 toabout 10% by weight.

“Binders” refers to substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose; starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 2 to about 20% by weight of the composition, morepreferably from about 3 to about 10% by weight, even more preferablyfrom about 3 to about 6% by weight.

“Lubricant” is meant to describe a substance added to the dosage form toenable the tablet, granules, etc. after it has been compressed, torelease from the mold or die by reducing friction or wear. Suitablelubricants include metallic stearates such as magnesium stearate,calcium stearate or potassium stearate; stearic acid; high melting pointwaxes; and water soluble lubricants such as sodium chloride, sodiumbenzoate, sodium acetate, sodium oleate, polyethylene glycols andd'l-leucine. Lubricants are usually added at the very last step beforecompression, since they must be present on the surfaces of the granulesand in between them and the parts of the tablet press. The amount oflubricant in the composition can range from about 0.2 to about 5% byweight of the composition, preferably from about 0.5 to about 2%, morepreferably from about 0.3 to about 1.5% by weight.

“Glidents” means materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

“Coloring agents” refers to excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes and food grade dyes adsorbed onto a suitable adsorbent such as clayor aluminum oxide. The amount of the coloring agent can vary from about0.1 to about 5% by weight of the composition, preferably from about 0.1to about 1%.

“Bioavailability” refers to the rate and extent to which the active drugingredient or therapeutic moiety is absorbed into the systemiccirculation from an administered dosage form as compared to a standardor control. Conventional methods for preparing tablets are known. Suchmethods include dry methods such as direct compression and compressionof granulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

The compounds of Formulae I and II can form salts which are also withinthe scope of this invention. Reference to a compound of Formulae I andII herein is understood to include reference to salts thereof, unlessotherwise indicated. The term “salt(s)”, as employed herein, denotesacidic salts formed with inorganic and/or organic acids, as well asbasic salts formed with inorganic and/or organic bases. In addition,when a compound of Formulae I and II contains both a basic moiety, suchas, but not limited to a pyridine or imidazole, and an acidic moiety,such as, but not limited to a carboxylic acid, zwitterions (“innersalts”) may be formed and are included within the term “salt(s)” as usedherein. Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of Formula I or may be formed, for example, byreacting a compound of Formulae I and II with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons or sulfurs on various substituents, including enantiomeric forms(which may exist even in the absence of asymmetric carbons), rotamericforms, atropisomers, and diastereomeric forms, are contemplated withinthe scope of this invention. For example, if a compound of Formulae Iand II incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention. Individual stereoisomers of the compounds of the inventionmay, for example, be substantially free of other isomers, or may beadmixed, for example, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate” “prodrug” and the like, is intendedto equally apply to the salt, solvate and prodrug of enantiomers,stereoisomers, rotamers, tautomers, racemates or prodrugs of theinventive compounds.

Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula I may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

Polymorphic forms of the compounds of Formulae I and II, and of thesalts, solvates and prodrugs of the compounds of Formulae I and II, areintended to be included in the present invention.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³H, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formulae I and II (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula I cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formulae I and II can beuseful as α2C adrenoreceptor agonists.

A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of thecompound of Formula I or Formula II. An especially preferred dosage isabout 0.01 to 25 mg/kg of body weight/day of a compound of Formula I orFormula II, or a pharmaceutically acceptable salt or solvate of saidcompound.

The compounds of this invention may also be useful in combination(administered together or sequentially) with one or more therapeuticagents such as, for example, glucocorticosteroids, PDE-4 inhibitors,anti-muscarinic agents, cromolyn sodium, H₁ receptor antagonists, 5-HT₁agonists, NSAIDs, angiotensin-converting enzyme inhibitors, angiotensinII receptor agonists, β-blockers, β-agonists (including both long andshort acting), leukotriene antagonists, diuretics, aldosteroneantagonists, ionotropic agents, natriuretic peptides, painmanagement/analgesic agents, anti-anxiety agents, anti-migraine agents,and therapeutic agents suitable for treating heart conditions, psychoticdisorders, and glaucoma.

Suitable steroids include prednisolone, fluticasone (including all estersuch as the propionate or furoate esters), triamcinolone,beclomethasone, mometasone (including any ester form such as mometasonefuroate), budasamine, ciclesonide betamethasone, dexamethasone,prednisone, flunisolide, and cortisone.

Suitable PDE-4 inhibitors include roflumilast, theophylline, rolipram,piclamilast, cilomilast and CDP-840.

Suitable antiimuscarinic agents include ipratropium bromide andtiatropium bromide.

Suitable H₁ antagonists include astemizole, azatadine, azelastine,acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine,cyclizine, carebastine, cyproheptadine, carbinoxamine,descarboethoxyloratidine, diphenhydramine, doxylamine, dimethindene,ebastine, epinastine, efletirizeine, fexofenadine, hydroxyzine,ketotifen, loratidine, levocabastine, meclizine, fexofenadine,hydroxyzine, ketotifen, loratadine, levocabastine, meclizine,mizolastine, mequitazine, mianserin, noberastine, norastemizole,picumast, pyrilamine, promethazine, terfenadine, tripelennamine,temelastine, trimeprazine or triprolidine.

Suitable anti-inflammatory agents include aspirin, diclofenac,diflunisal, etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, andtolmetin.

Suitable aldosterone antagonists include spironolactone.

Suitable ionotropic agents include digitalis.

Suitable angiotensin II receptor agonists include irbesartan andlosartan.

Suitable diuretics include spironolactone, methyclothiazide, bumetanide,torsemide, hydroflumethiazide, trichlormethiazide, hydroclorothiazide,triamterene, ethacrynic acid, methyclothiazide, hydrochlorothiazide,benzthiazide, hydrochlorothiazide, quinethazone, hydrochlorothiazide,chlorthalidone, furosemide, indapamide, hydroclorothiazide, triamterene,trichlormethiazide, hydrochlorothiazide, amiloride HCl, amiloride HCl,metolazone, trichlormethiazide, bendroflumethiazide,hydrochlorothiazide, polythiazide, hydroflumethiazide, chlorthalidone,and metolazone.

Suitable pain management/analgesic agents include Celecoxib,amitriptyline, ibuprofen, naproxen, gabapentin, tramadol, rofecoxib,oxycodone HCl, acetaminophenoxycodone HCl, carbamazepine, amitriptyline,diclofenac, diclofenac, etodolac, fenoprofen calcium, flurbiprofen,ibuprofen, indomethacin, ketoprofen, ketorolac tromethamine, mefenamicacid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac,tolmetin sodium, valdecoxib, diclofenac/misoprostol, oxycontin, vicodin,darvocet, percocet, morphine sulfate, dilaudid, stadol, stadol NS,acetaminophen with codeine, acetaminophen with codeine #4, Lidoderm®patches, ziconotide, duloxetine, roboxetine, gabapentin and pregabalin.

Suitable β-blockers include acebutolol, atenolol,atenolol/chlorthalidone, betaxolol, bisoprolol fumarate,bisoprolol/HCTZ, labetolol, metoprolol tartrate, nadolol, pindolol,propranolol, propranolol/HCTZ, sotalol, and timolol.

Suitable β-agonists include dobutamine, ritodrine, salbutamol,levalbuterol, metaproternol, formoterol, fenoterol, bambuterol,brocaterol, clenbuterol, terbutaline, tulobuterol, epinephrine,isoprenalin, and hexoprenalin.

Suitable leucotriene antagonists include levamisole.

Suitable anti-migraine agents include rovatriptan succinate, naratriptanHCl, rizatriptan benzoate, sumatriptan succinate, zolmitriptan,almotriptan malate, methysergide maleate, dihydroergotamine mesylate,ergotamine tartrate, ergotamine tartrate/caffeine, Fioricet®,Fiorninal®, Depakene®, and Depakote®.

Suitable anti-anxiety and anti-depressant agents include amitriptylineHCl, bupropion HCl, citalopram hydrobromide, clomipramine HCl,desipramine, fluoxetine, fluvoxamine maleate, maprotiline HCl,mirtazapine, nefazodone HCl, nortriptyline, paroxetine HCl,protriptyline HCl, sertraline HCl, doxepin, and trimipramine maleate.

Suitable angiotensin converting enzyme inhibitors include Captopril,enalapril, enalapril/HCTZ, lisinopril, lisinopril/HCTZ, and Aceon®.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which are described later have been carried outwith the compounds according to the invention and their salts.

This invention is also directed to pharmaceutical compositions whichcomprise at least one compound of Formula I or Formula II, or apharmaceutically acceptable salt or solvate of said compound and atleast one pharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.When preparing a liquid preparation, the inclusion of one or moresolubility enhancing components is excluded. Solubility enhancingcomponents are described, for example, in U.S. Pat. No. 6,673,337 incolumn 2, line 50 to column 3, line 17 and in column 6, line 49 to line31; U.S. Pat. No. 6,673,337 is expressly incorporated by reference.Specific solubility enhancing agents that are excluded in the liquidform preparations include metal carboxymethylcelluloses, metalcarboxymethylhydroxyethylcelloses, hydroxypropylmethyl cellulosesderivative of these compounds, and cyclodextrins. As an example may bementioned water or water-propylene glycol solutions for parenteralinjection or addition of sweeteners and opacifiers for oral solutions,suspensions and emulsions. Liquid form preparations may also includesolutions or suspensions for intranasal administration.

An aspect of this invention is that the pharmaceutical composition is ina solid dosage form comprising a compound of Formulae I and II or apharmaceutical acceptable salt, ester, solvate or prodrug thereof and aleast one pharmaceutically acceptable carrier, adjuvant or vehicle.

Another aspect of this invention is a liquid, aqueous pharmaceuticalcomposition is comprising a compound of Formulae I and II or apharmaceutical acceptable salt, ester, solvate or prodrug thereof and aleast one pharmaceutically acceptable carrier, adjuvant or vehicleprovided that the adjuvant is not a solubility enhancing component, suchas those described in U.S. Pat. No. 6,673,337 (discussed above).

Another aspect of this invention is a liquid, aqueous pharmaceuticalcomposition is comprising a compound of Formulae I and II or apharmaceutical acceptable salt, ester, solvate or prodrug thereof and aleast one pharmaceutically acceptable carrier, adjuvant or vehiclewherein if a solubility enhancement component is present it iscyclodextrin.

Another aspect of this invention is a pharmaceutical formulation that isa nasal spray wherein the pH is equal to or less that about 6.5, morepreferably between about 6.1 to 6.2.

Another aspect of this invention the formulation is a nasal spraywherein the adjuvants include a suspending agent (e.g., AVICEL (such asAVICIL RC-581, RC-591 and CL-611), which are microcrystalline celluloseand carboxymethylcellulose sodium; hydroxypropylmethyl cellulose; methylcellulose; polyvinyl alcohol; or CARBOPOL) and a humectant (e.g.,glycerin, propylene glycol; polyethylene glycol; povidone; or dextrose).

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions or suspensions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formulae I and II, or apharmaceutically acceptable salt or solvate of said compound and apharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formulae I and II, or a pharmaceuticallyacceptable salt or solvate of said compound and an amount of at leastone therapeutic agent listed above, wherein the amounts of the two ormore ingredients result in desired therapeutic effect.

In general, the compounds in the invention may be produced by a varietyof processes know to those skilled in the art and by know processesanalogous thereto. The invention disclosed herein is exemplified by thefollowing preparations and examples which should not be construed tolimit the scope of the disclosure. Alternative mechanistic pathways andanalogous structures will be apparent to those skilled in the art. Thepractitioner is not limited to these methods.

One skilled in the art will recognize that one route will be optimizeddepending on the choice of appendage substituents. Additionally, oneskilled in the art will recognize that in some cases the order of stepshas to be controlled to avoid functional group incompatibility.

The prepared compounds may be analyzed for their composition and purityas well as characterized by standard analytical techniques such as, forexample, elemental analysis, NMR, mass spectroscopy and IR spectra.

One skilled in the art will recognize that reagents and solventsactually used may be selected from several reagents and solvents wellknown in the art to be effective equivalents. Hence, when a specificsolvent or reagent is mentioned, it is meant to be an illustrativeexample of the conditions desirable for that particular reaction schemeand in the preparations and examples described below.

Where NMR data are presented, ¹H spectra were obtained on either aVarian VXR-400 (400 MHz, ¹H), Varian Gemini-300 (300 MHz), VarianMercury VX-400 (400 MHz), or Bruker-Biospin AV-500 (500 MHz), andchemical shifts are reported as ppm with number of protons andmultiplicities indicated parenthetically. Where LC/MS data arepresented, analyses was performed using an Applied Biosystems API-100mass spectrometer and C18 column, 10-95% CH₃CN—H₂O (with 0.05% TFA)gradient. The observed parent ion is given.

The following solvents and reagents may be referred to by theirabbreviations in parenthesis:

-   Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; t-Bu=tert-butyl;    Ph=phenyl, and Ac=acetyl-   μl=microliters-   AcOEt or EtOAc=ethyl acetate-   AcOH or HOAc=acetic acid-   ACN=acetonitrile-   aq=aqueous-   atm=atmosphere-   Boc or BOC=tert-butoxycarbonyl-   BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   cat=catalyst or catalytic-   Cbz=benzyloxycarbonyl-   DEA=diethylamine-   DEAD=diethylazodicarboxylate-   DCM or CH₂Cl₂: dichloromethane:-   DMAP=4-dimethylaminopyridine-   DIBAL=diisobutylaluminum hydride-   DIPEA=diisopropylethylamine-   DME=1,2-dimethoxyethane-   DMF=dimethylformamide-   DMS=dimethylsulfide-   DMSO=dimethyl sulfoxide-   Dppf=1,1′-bis(diphenylphosphino)ferrocene-   EDCI or DEC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Eq=equivalents-   g=grams-   h or hr=hour-   HOBt=1-hydroxybenzotriazole-   IPA=isopropyl alcohol-   Im=imidazole-   LAH=lithium aluminum hydride-   LDA=lithium diisopropylamide-   LCMS=liquid chromatography mass spectrometry-   M=molar-   mCPBA=m-chloroperoxybenzoic acid-   min=minute-   mg=milligrams-   mL=milliliters-   mmol=millimoles-   MeOH=methanol-   MS=mass spectrometry-   N=normal-   NBS=N-bromosuccimide-   NMO=N-methylmorpholine N-oxide-   NMR=nuclear magnetic resonance spectroscopy-   PG=protecting group-   Pyr=pyridine-   rac or (±)=racemic mixture or enantiomers-   RT or rt=room temperature (ambient, about 25° C.)-   sat=saturated-   SFC=supercritical fluid chromatography-   SM=starting material-   TBSCl=t-butyldimethylsilyl chloride-   TBS=t-butyldimethyl silyl-   TEA=triethylamine (Et₃N)-   TEMPO=2,2,6,6-Tetramethylpiperidine-1-oxyl-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography-   TMS=trimethylsilyl-   Tos or Ts=p-toluenesulfonyl (tosyl)-   Tol=toluene-   TosMIC=Toluenesulfonylmethyl isocyanide-   TPAP=tetrapropylammonium perruthenate-   Tr=triphenylmethyl

EXAMPLES

The compounds of this invention can be prepared through the generalapproach outlined in the following schemes. These schemes are beingprovided to illustrate the present invention. While the schemes depictJ¹-J⁴ as —CH—, wherein the hydrogen may be replaced by A, this is forexemplary purposes only and one of ordinary skill in the art would beable to prepare compounds containing one of the other definitions forJ¹-J⁴ by modifying schemes using other procedures known to one in theart. To assist one in this endeavor the ordinary practitioner would havefull knowledge of literature sources such as Chemical Abstracts,Beilstein, etc.

Scheme 1 shows an approach in which S1 (X=—CH₂— and n=0-2; or X=O—, —NH—or substituted N and n=1-2) is converted to hydantoin S2 by reactionwith ammonium carbonate and a cyanide source (such as KCN, NaCN orTMSCN; or related conditions such as CO₂/NH₄OH/NaCN/H₂O₂). Subsequenthydrolysis to the amino acid S3a with base (LiOH, NaOH, Ba(OH)₂, or thelike) is followed by conversion to the amino ester S3b and reduction tothe alcohol S4 (with reagents such as as DIBAL, NaBH₄, borane, or LAH).Alternatively, the amino acid S3a is directly reduced to S4. In variousembodiments, the amino alcohol (S4) is then cyclized to provide thefollowing moieties:

-   -   substituted 2-aminooxazoline S5a (Z=NHC(O)R), with an        isothiocyanate (such as benzoyl isothiocyanate).    -   2-aminooxazoline S5b (Z=NH₂ via treatment with, for example,        cyanogen bromide with or without a base (such as        diisopropylethylamine) or by treatment with an thioisocyanate,        such as (EtO₂C)NCS or BzNCS, followed by treatment with a base        or acid or catalyst such as Hg(O), Hg(OAc)₂ or        2-chloro-3-ethylbenzoxazolium tetrafluoroborate and hydrolysis        with LiOH);    -   oxazoline S5c (Z=H, by treatment with methyl formate/DAST,        trialkoxyformate, dimethylformamide dimethyl acetal or other        similar reagent);    -   oxazolidinone (S5d, Z=OH) by treatment with reagents known in        the literature (e.g., carbonyldiimidazole, triphosgene, or        related carbonates or chloroformates etc.);    -   oxazolidinethione (S5e, Z=SH, by treatment with a known reagent        such as EtOCS₂H, Im₂CS, CS₂, Cl₂CS, NaSCH, or MeSC(S)OEt etc.);        and    -   an oxazoline S5f with a carbon linkage at Z (by numerous        literature methods such as treatment with RC(═NH)OEt, RCN/ZnCl₂,        RCO₂H, RC(OMe)₃ an anhydride, RCHO with an appropriate oxidant        or other methods).

2-aminooxazoline S5b (Z=NH₂) may also be obtained from S5a (Z=NHC(O)R),by treatment with a hydroxide source such as LiOH. Oxazolidinethione S5e(Z=SH) may also be obtained from 5d (Z=OH) by treatment with a sulfurreagent (such as Lawesson's reagent). The oxazolidinone (S5d, Z=OH) oroxazolidinethione (S5e, Z=SH) may be further substituted by alkylationor acylation chemistry known in the literature (to Z=OR or Z=SRrespectively). An alkylated oxazolidinethione (S5e, Z=SR, where R=alkylor the like) is optionally oxidized to provide Z=S(O)_(p)R (where p=1 or2).

The biaryl coupling transformation (A=halogen or activated alcohol toA=the various definitions of R¹, such as aryl, cycloalkenyl,heterocyclenyl, or heteroaryl) occurs via a metal catalyzed ormetal-facilitated process (such as Stille coupling, Suzuki coupling,Negishi coupling or nucleophilic substitution reaction) with anappropriately substituted aryl or heteroaryl partner. Installation ofthe biaryl group may be done at various stages in the sequence.

The functionalized R² and R³ groups may exist in the starting materialS1 or its precursor. Alternatively, S1 or its precursor may befunctionalized with R² and R³ groups at various stages in the sequence.

According to another embodiment (Scheme 2), compound S1 is converted toS6 by a Strecker reaction (with a cyanide source and an amine such asNH₄Cl/KCN or alkylamine/NaCN). The nitrile is reduced (with LAH or asimilar reagent) to S7, which may be cyclized to provide S8 or S9. Inanother embodiment, compound S6 is converted to amino acid S3a(Scheme 1) by hydrolysis.

According to another embodiment (Scheme 3), compound S5d or S5e isconverted to S10 (via chlorination with SOCl₂, POCl₃, PCl_(S), PCl₅, Cl₂or the like). In various embodiments, intermediate S10 is displaced withan amine, oxygen or carbon nucleophile or alternatively reacted in ametal catalyzed or metal-facilitated process (such as apalladium-catalyzed Suzuki or Stille coupling) to provide S5 (in which Zis a carbon, oxygen or nitrogen linked substituent).

Scheme 4 shows an approach in which amino alcohol S4 is reacted with anacid under standard coupling conditions (with reagents such as EDCI,HOBt etc.) or with an acid chloride to provide the amide S11 (wherein Ris defined as Z in Formula I or a group that may be converted into Z).In one embodiment, compound S11 is then treated with sulfur reagent suchas Lawesson's Reagent, P₂S₅, or Deoxy-Fluor to affect incorporation of Swith concomitant cyclization to S12. Alternatively, S4 may be convertedto thioamide or thiourea S13 (by reaction with a thioester, thioacid, orthioisocyanate) and then cyclized to S12 (under a variety of conditionsincluding treatment with HCl, SOCl₂, Deoxy-Fluor, DAST, Hg(0), Hg(OAc)₂or 2-chloro-3-ethylbenzoxazolium tetrafluoroborate or other reagents).In another embodiment, S11 is first converted to S13 (by treatment witha sulfur reagent such as Lawesson's Reagent, DAST or the like) and thencyclized to S12 in a step-wise fashion.

According to another embodiment (Scheme 5), aminoester S3b (optionallyprotected) is sequentially treated with an organometallic reagent (suchas a RMgBr, a Grignard reagent, or RLi, an alkyllithium compound, togive a ketone S15), followed by reduction to afford S17 (wherein R isdefined as R⁴ in Formula I or a group that may be converted into R⁴).The substituted aminoalcohol S17 is then cyclized to a substitutedoxazoline S18 as previously described. Alternatively, this generalapproach may be taken starting with the amino nitrile S6 or Weinrebamide S14 (accessed from aminoacid S3a by amide coupling with HN(Me)OMeor from aminoester S3b reaction with HN(Me)OMe/AlMe₃). In anotherembodiment, S3b, S6, or S14 are reduced (or reduced/oxidized) toaldehyde S16 which is then subsequentially reacted with anorganometallic reagent to provide S17. The reduction of ketone S15 mayoptionally be undertaken in a stereoselective manner to preferentiallyprovide one stereoisomeric alcohol S17. Reagents for a stereoselectivereduction are well known in the art, and include, but are not limited tothe CBS-oxazaborolidine/borane reagent, LAH/N-methylephedrine, BINAL-H,Ipc₂BCl, DIBAL-H, Li-selectride, NaBH₄/CeCl₃, and enzymatic catalysis.

According to another embodiment (Scheme 6), ketone S15 (optionallyprotected) undergoes an olefination (Wittig, Horner-Emmons, Tebbereaction etc.)-hydroboration sequence to provide alcohol S20 (wherein Ris defined as R⁴ in Formula I or a group that may be converted into R⁴),which is then cyclized to S21.

According to another embodiment (Scheme 7), ketone S15 (optionallyprotected) undergoes an olefination (Wittig, Horner-Emmons etc.) to a1,2-disubstituted olefin. Hydroboration of S22 (wherein R and R′ areindependently defined as R⁴ in Formula I or a group that may beconverted into R⁴) provides alcohol S23, which is then cyclized to S24.

According to another embodiment (Scheme 8), alcohol S20 (optionallyprotected) is sequentially oxidized and treated with an organometallicreagent to provide S23 (wherein R and R′ are independently defined as R⁴in Formula I or a group that may be converted into R⁴). Compound S23 isthen cyclized to provide S24.

According to another embodiment (Scheme 9), chiral alcohol S28 isprepared by the addition of the anion of a chiral sulfoxide S27 ontoketone S26. An intramolecular S_(N)2 reaction provides epoxides S29,which are opened using nitrogen nucleophiles such as ammonia or byaddition of NH₂ precursors such as azides, phthalimides, benzyl aminesor benzhydryl amines to give aldehyde S30. Alcohols S31 and S32 areprepared by addition of an organometallic compound (such as anorganomagnesium) and amine deprotection.

In another embodiment (Scheme 10), chiral sulfoxide S33 contains analkyl group R′. Following an approach similar to Scheme 9, epoxideopening provides ketone S36. Alcohols S31 and S32 are obtained byreduction of the ketone by known methods (such as treatment with asNaBH₄) and amine deprotection. Alternatively, the ketone is reduced inan asymmetrical fashion using chiral reduction methods known for thoseskilled in the art (such as CBS reduction).

According to another embodiment (Scheme 11), compound S1 is treated witha chiral amine (such as (R)-phenylglycine or other chiral amine) andthen treated with a cyanide source (such of KCN, NaCN or TMSCN) toprovide converted to S6 as a pure enantiomer or in enantiomericallyenriched form. Reduction of the nitrile, cleavage of the chiralauxiliary, and cyclization provides imidazoline S8 as previouslydescribed. Alternatively, S6 is converted to S3b by hydrolysis (withMeOH/HCl or other approach) and cleavage of the chiral auxiliary.

According to another embodiment (Scheme 12), the ester S3b is convertedto amide S3c (by treatment with ammonia or an amine) and then reduced(with LAH, BH₃ or a similar reagent) to diamine S38, which may becyclized to provide:

-   -   S39a, via treatment with amidine reagents such as formamidine,        acetamidine, or benzamidine);    -   S39b, via treatment with diphenyl cyanocarbonimidate;    -   S39c, via treatment with cyanogen bromide; and    -   S39d, via treatment with carbonyldiimidazole, triphosgene, or        related carbonates or chloroformates etc.).

According to another embodiment (Scheme 13), a functionalized xylene 40b(R=LG such as Br, synthesized from S40a with NBS or similar) iscondensed with a N-protected glycine ester (such asN-(diphenylmethylene)glycine ethyl ester or N-benzylideneglycine ethylester) to provide S41 which is further elaborated to S42. Use of chiralN-protected glycine ester or use of a chiral phase-transfer catalystwith a nonchiral N-protected glycine ester provides enantioselectiveenhancement in the condensation.

Alternatively, S40b is condensed with a malonate ester (such as dimethylmalonate) to provide S43. Selective enzymatic hydrolysis of one ester(by an esterase or similar enzyme) provides S44 which is converted toS45 by a Curtuis rearrangement and then further elaborated to S42.

The starting materials, including compound S1, S26, and S40, andreagents used in preparing compounds described are either available fromcommercial suppliers such as Aldrich Chemical Co. (Wisconsin, USA) andAcros Organics Co. (New Jersey, USA) or were prepared by literaturemethods known to those skilled in the art. When unavailable fromcommercial suppliers, compound S1 (optionally substituted with R² andR³, or with substituents that are converted into R² and R³) issynthesized from S46, S47, S48, S49, or other starting materialsaccording to methods known in the literature.

Compounds of formulae S5, S8, S9, S10, S12, S18, S21, S24, S39, S42 andS45 can be prepared by the general methods outlined above. Exemplarycompounds were prepared as described in the examples below or fromstarting materials known in the art. These examples are being providedto further illustrate the present invention. They are for illustrativepurposes only; the scope of the invention is not to be consideredlimited in any way thereby.

Preparative Example 1

Step 1

A mixture of 8-bromo-2-tetralone (5.0 g, 22.2 mmol), (NH₄)₂CO₃ (15.0 g,156 mmol), and KCN (2.16 g, 33.2 mmol) in 1:1 EtOH—H₂O (50 mL) washeated in a sealed tube overnight at 85° C. The reaction was then cooledto RT, diluted with water (˜400 mL) and stirred for 2 h. The precipitatewas filtered and dried in vacuo overnight to provide hydantoin 1A (5.95g, 91%). LCMS m/z 295 (MH+).

Steps 2-3

A mixture of 1A (4.46 g, 15.1 mmol) and LiOH—H₂O (3.18 g, 75.6 mmol) inH₂O (100 mL) was refluxed overnight. The reaction was then cooled to 0°C., acidified with 12 N HCl, and concentrated to give the amino acid asa solid. LCMS m/z 270 (MH+).

Thionyl chloride (9 mL) was carefully added to MeOH (300 mL) at 0° C.The resulting mixture was then added to a flask charged with the aminoacid product. The reaction was heated to reflux overnight and thencooled and concentrated. The residue was taken up in sat. aq. NaHCO₃ andextracted EtOAc (2×). The combined organic layers were dried over Na₂SO₄and concentrated. Chromatography (0-50% EtOAc/hex) provided 1B as a redoil. LCMS m/z 284 (MH+).

Steps 4-5

Compound 1B (8.16 g, 28.7 mmol) was dissolved in anhydrous MeOH and thentreated with NaBH₄ (2.72 g, 71.8 mmol, bubbling and heat generationnoted). A second portion of NaBH₄ (2.72 g, 71.8 mmol) was added after 15min. The reaction was concentrated after TLC indicated consumption of 1B(˜15 min). THF (100 mL) was added to the residue and then removed invacuo to give the yellow foam 1C, which was used in the next stepwithout purification or aqueous workup. LCMS m/z 256 (MH+).

The crude aminoalcohol 1C (˜28.7 mmol) was dissolved in anhydrous THF(250 mL) and treated with benzoyl isothiocyanate (8.5 mL, 63 mmol).After stirring for 20 min at RT, additional benzoyl isothiocyanate (4.3mL, 32 mmol) was added. The reaction was concentrated after TLC and MSindicated consumption of 1C (˜20 min). The residue was diluted withwater and extracted with DCM (3×). The combined organic layers weredried over Na₂SO₄, concentrated and chromatographed (20-40% EtOAc/hex)to provide provided 1D as a yellow foam. LCMS m/z 385 (MH+).

Step 6

A mixture of 1D (˜38.7 mmol) and LiOH—H₂O (6.03 g, 144 mmol) in 1:1MeOH—H₂O (200 mL) was refluxed for 1.5 h. The reaction was concentratedto one-half volume and extracted with DCM (4×). The combined organiclayers were dried over Na₂SO₄, concentrated and chromatographed (2% ofNH₃-MeOH/DCM) to give the desired product 1E (white solid 2.49 g, ˜38%for 3-steps, LCMS m/z 281 MH+) and a small amount of a byproduct fromStep 5 (1F, LCMS m/z 298 MH+).

Step 7

A mixture of 1E (3.03 g, 10.8 mmol), pyrimidine-5-boronic acid (2.00 g,16.2 mmol), Pd(PPh₃)₄ (1.25 g, 1.08 mmol), K₂CO₃ (2.98 g, 21.6 mmol) in1:1 DMF-H₂O (60 mL) were heated at 110° C. in a sealed tube for 1 h. Thereaction concentrated, diluted with water and extracted with DCM (4×).The layers were separated. The combined organic layers were dried overNa₂SO₄, concentrated and chromatographed (2-5% of NH₃-MeOH/DCM) to givethe title compound (±)-1 (2.74 g, 90%). LCMS m/z 281 (MH+).

The pure single enanatiomers (2D and 2E) of compound (±)-1 wereseparated as described in Example 2. Alternatively, the pure enantiomersof compound ID were also separated by chiral prep HPLC. An alternativesynthesis of compound (±)-1 is given in Example 6.

In a manner similar to that described above, 1E was coupled with anappropriate aryl boronic acid or aryl boronic ester to provide thefollowing compounds:

Cmpd No. Compound LCMS (MH+) (±)-1G

279 (±)-1H

280

Preparative Example 2

Step 1

A mixture of compound (±)-1 (2.74 g, 9.77 mmol), CbzCl (3.5 mL, 24.4mmol), TEA (4.1 mL, 29.3 mmol) and DMAP (0.24 g, 1.95 mmol) in DCM (100mL) was stirred at RT for 30 min and then treated with additionalportions of CbzCl (3.5 mL, 24.4 mmol) and TEA (4.1 mL, 29.3 mmol). After1 h, the reaction was concentrated, treated with water and extractedwith DCM (4×). The organic layer was dried over Na₂SO₄, filtered,concentrated and chromatographed (2% MeOH/DCM) to provide (±)-2A.

Steps 2-3

The racemic mixture (±)-2A was separated on a preparative Chiralpak ADcolumn with 50% isopropanol-hexanes to provide the pure enantiomers 2B(>95% ee) and 2C (>95% ee). The enantiomers 2B and 2C were eachsubjected to hydrogenation with Pd/C and H₂ (40 psi, overnight, MeOH),followed by chromatography (5% NH₃-MeOH/DCM) to provide 2D (enantiomer Aof 1; LCMS m/z 281, MH+) and 2E (enantiomer B of 1; LCMS m/z 281, MH+),respectively. The HCl salts of 2D and 2E could each be made by stirringin 4N HCl-dioxane followed by concentration.

Preparative Example 3

Step 1

A mixture of compound 1C (0.25 g, 0.98 mmol), Boc₂O (0.24 g, 1.07 mmol),and Et₃N (0.4 mL, 2.9 mmol) in DCM (10 mL) was stirred at RT overnightand then concentrated. Chromatography (2-10% NH₃-MeOH/DCM) provided 3A(300 mg, 86%).

Step 2

A mixture of 3A (70 mg, 0.20 mmol),2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester, (98 mg, 0.39mmol), Pd(dppf)Cl₂—CH₂Cl₂ (16 mg, 0.02 mmol), K₃PO₄ (125 mg, 0.59 mmol)in 3:1 DME-H₂O (2 mL) were microwaved at 120° C. for 15 min. Thereaction was diluted with EtOAc and washed with water (3×). The organiclayer were dried over Na₂SO₄, concentrated and chromatographed (2% ofNH₃-MeOH/DCM) to give 3B (50 mg, 65%) as a yellow solid. LCMS m/z 399(MH+).

Step 3

Compound 3B (50 mg, 0.12 mmol) was taken up in DCM (5 mL) and treatedwith TFA (1 mL). The reaction was stirred at RT for 2 h, concentrated,and chromatographed (5-10% of NH₃-MeOH/DCM) to give 3C. LCMS m/z 299(MH+).

Step 4

A mixture of 3C (40 mg, 0.13 mmol) and cyanogen bromide (17 mg, 0.16mmol) in DCM (5 mL) was stirred overnight at RT and concentrated.Chromatographed (C18, 10-90% MeCN/H₂O with 0.1% TFA) to give the titlecompound (±)-3. LCMS m/z 324 (MH+).

Following an analogous sequence to that described above, the followingcompound was prepared:

Cmpd No. Compound LCMS (MH+) (±)-3D

306

Preparative Example 4

Compound (±)-4 was prepared from 7-bromo-2-tetralone in a manner similarto that described in Example 1: hydantoin formation with (NH₄)₂CO₃/KCN,hydrolysis with LiOH, methyl ester formation with SOCl₂/MeOH, reductionwith NaBH₄, cyclization with benzoyl isothiocyanate, and hydrolysis withLiOH to provide 4D (LCMS m/z 281/283, MH+). Final Suzuki coupling withpyrimidine-5-boronic acid/Pd(PPh₃)₄ afforded the title compound (±)-4.LCMS m/z 281 (MH+).

Preparative Example 5

The starting material 6-bromochroman-3-one (5A) was prepared from6-bromochroman-4-one in a manner similar to that described in theliterature (Synthesis, 1980, 621): 6-bromochroman-4-one was reduced withNaBH₄ (1.2 eq, MeOH-DCM, 0° C. to RT, 2 h) and then eliminated withpTsOH (cat., toluene, reflux, 3 h, 90% for 2-steps). The resulting6-bromochromene was subjected to osmylation (cat. OsO₄, 1 eq. NMO,water-acetone-tBuOH, RT, overnight) and subsequent treatment with pTsOH(cat., toluene, reflux, 15 min, 86% for 2-steps) to provide6-bromochroman-3-one (5A).

Compound (±)-5D was prepared from 6-bromochroman-3-one in a mannersimilar to that described in Example 1: hydantoin formation with(NH₄)₂CO₃/KCN, hydrolysis with LiOH, methyl ester formation withSOCl₂/MeOH, reduction with NaBH₄, cyclization with benzoylisothiocyanate, and hydrolysis with LiOH. A small amount of compound 5E(LCMS m/z 300/302, MH+) was formed during the benzoyl isothiocyanatecyclization step. The title compound (±)-5 was prepared from (±)-5D viaSuzuki coupling with pyrimidine-5-boronic acid/Pd(dppf)Cl₂ in a mannersimilar to that described in Example 3 (Step 2). LCMS m/z 283 (MH+).

Alternatively, and in a manner similar to that that described in Example3 (Step 4), compound 5C was reacted with 1.2 eq. cyanogen bromide (4 h,RT, EtOH) to directly provide (±)-5D (LCMS m/z 283/285, MH+) in ˜50%yield with ˜40% recovered starting material 5C.

In a manner similar to that described above, 5D was coupled with anappropriate aryl boronic acid or aryl boronic ester to provide thefollowing compounds:

Cmpd LCMS No. Compound (MH+) (±)-5F

285 (±)-5G

299 (±)-5H

300 (±)-5I

301 (±)-5J

296 (±)-5K

281 (±)-5L

309 (±)-5M

349 (±)-5N

311 (±)-5P

282 (±)-5Q

312 (±)-5R

296 (±)-5S

271 (±)-5T

287 (±)-5U

313 (±)-5V

271 (±)-5W

321

Preparative Example 6

An alternative synthesis of (±)-1 is given below:

Step 1

To a solution of 8-methoxy-2-tetralone (600 mg, 3.4 mmol) in EtOH—H₂O(1:1, 12 mL) in a sealed tube was added ammonium carbonate (2.28 g, 23.8mmol) and KCN (420 mg, 6.8 mmol) in one portion. The mixture was heatedat 80° C. for 12 h before it was cooled to RT. Water (20 mL) was addedto precipitate the product 6A. The light grey solid was collected byfiltration and washed with water and dried in air (835 mg, 100%, LCMSm/z 247, MH+).

Steps 2-3

A suspension of 6A (200 mg, 0.813 mmol) and Ba(OH)₂ (460 mg, 3.25 mmol)in water (2 mL) was heated in a sealed tube at 120° C. for 36 h. Themixture was acidified with 6 N H₂SO₄, and filtered and the filter padwas washed with MeOH repeatedly. The combined filtrate was concentratedunder reduced pressure to yield the amino acid as an off-white solid.The crude product was added to a mixture of SOCl₂ (145 mg, 1.219 mmol)and MeOH (10 mL). The mixture was stirred at reflux for 3 h, cooled toRT and concentrated under reduced pressure. The methyl ester HCl saltwas suspended in EtOAc (20 mL) and neutralized with sat. NaHCO₃. Theaqueous phase was extracted with EtOAc (2×10 mL). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue was purified by column chromatography (80%EtOAc/Hexanes) to give 6B as a pale yellow oil (105 mg, 55%, LCMS m/z236, MH+).

Step 4

To a stirred solution of 6B (3.17 g, 13.5 mmol) in THF (50 mL) was addedLiAlH₄ (1.02 g, 27 mmol) in small portions at 0° C. The mixture wasstirred at RT overnight and quenched with slow addition of water (1 mL),1 N NaOH (3 mL) and water (1 mL). The grey suspension was filtered andthe filtrate was dried (Na₂SO₄), filtered and concentrated under reducedpressure to yield compound 6C (2.79 g, 100%, LCMS m/z 208, MH+) as awhite solid.

Step 5

To a stirred solution of 6C (2.79 g, 13.5 mmol) in CH₂Cl₂ (25 mL) wasadded BBr₃ (1M CH₂Cl₂ solution, 32.5 mL) at 0° C. The bright yellowsolution was stirred at this temperature for 3 h and quenched withaddition of sat. NaHCO₃ until pH equals 7. The mixture was concentratedunder reduced pressure to give an off-white solid. To a solution of thecrude phenol in dioxane-H₂O (1:1, 25 mL) was added Boc₂O (5.9 g, 27mmol) and NaHCO₃ (1.7 g, 20.25 mmol). The mixture was stirred overnight,acidified with 1 N HCl, and extracted with EtOAc (4×60 mL). The combinedorganic layers were washed with brine (10 mL), dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography (50% EtOAc/Hexanes) to give compound 6D as paleyellow oil (2.555 g, 64%, LCMS m/z 294, MH+).

Step 6

To a solution of 6D (1.555 g, 5.3 mmol) in THF (20 mL) was addedtriethylamine (2.2 mL, 15.9 mmoL) and PhNTf₂ (2.276 g, 6.37 mmol). Thesolution was stirred at RT overnight and concentrated under reducedpressure. The residue was purified by column chromatography (50%EtOAc/Hexanes) to give compound 6E as a white solid (1.99 g, 85%).

Step 7

To a solution of 6E (1.45 g, 3.4 mmol) in DMF (2 mL) was added TBSCl(614.9 mg, 4.08 mmol) and imidazole (554.9 mg, 8.16 mmol). The mixturewas stirred at RT overnight and quenched with addition of water (30 mL).This was extracted with EtOAc (30 mL) and the resulting organic phasewas washed with H₂O (3×30 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (5% EtOAc/Hexanes) to give compound 6Fas a pale yellow oil (1.759 g, 96%, LCMS m/z 540, MH+).

Step 8

To a solution of 6F (91.8 mg, 0.17 mmol) in DME-water (3:1, 1.6 mL) wasadded Pd(PPh₃)₄ (19.7 mg, 0.017 mmol), 5-pyrimidylboronic acid (31.6 mg,0.255 mmol), and NaHCO₃ (1 M solution, 0.34 mL). The mixture was heatedusing microwave (120° C., 15 min) and treated with EtOAc (15 mL) and 1 NNaOH (5 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (15% EtOAc/Hexanes) to give compound 6G as a white solid(71 mg, 89%, LCMS m/z 470, MH+).

Step 9

To a stirred solution of 6G (772 mg, 1.646 mmol) in MeOH (5 mL) wasadded HCl (4 M in dioxane, 8.23 mL, 32.9 mmol). The mixture was stirredat RT for 4 h and concentrated under reduced pressure. The residue waspurified by column chromatography (10% MeOH/CH₂Cl₂, 1% NH₄OH) to givecompound 6H as a white solid (277.9 mg, 66%).

Step 10

To a stirred solution of 6H (91.2 mg, 0.355 mmol) in EtOH (2 mL) wasadded BrCN (45.1 mg, 0.426 mmol) at 0° C. The mixture was stirred at RTfor 4 h and concentrated under reduced pressure. The residue waspurified by prep-HPLC (0-50% CH₃CN/H₂O) to give compound (±)-1 as awhite solid (35.8 mg, 36%, LCMS m/z 281, MH+) and recovered 6H (45.6 mg,50%).

In a separate experiment, a mixture of compound 6H (0.076 mmol) and BrCN(5M/CH₃CN, 18 μL, 0.091 mmol) in CH₃CN (0.8 mL) was stirred overnight,treated with an additional BrCN (1 eq) and TEA (1 eq) and then stirredan additional 18 h to provide (±)-61 as the major product. LCMS m/z 306(MH+).

In a manner analogous to that described above (Steps 6-8), 6F wascoupled with an appropriate aryl boronic acid or aryl boronic ester andthen further elaborated to provide the following compounds:

Cmpd. No. Compound LCMS (MH+) (±)-6J

304 (±)-6K

304 (±)-6L

283

Preparative Example 7

In a manner similar to that described in Example 6 (Steps 1-10), thefollowing compounds were synthesized from 5-methoxy-2-tetralone:

Cmpd No. Compound LCMS (MH+) (±)-7A

283 (±)-7B

281 (±)-7C

298

Preparative Example 8

Steps 1-2

In a manner similar to that described in Example 1 (Step 1), 2-indanonewas treated with (NH₄)₂CO₃ and KCN to provide hydantoin 8A. Thehydantoin was subjected to bromination (HBr/Br₂) as described inWO2004/082602 to provide 8B.

Steps 3-5

In a manner similar to that described in Example 1 (Steps 2-4), compound8B was sequentially treated with LiOH, SOCl₂-MeOH, and NaBH₄ to provide8C.

Steps 6-7

In a manner similar to that described in Example 3 (Steps 4 and 2),compound 8C was sequentially cyclized with cyanogen bromide and thencoupled with pyrimidine-5-boronic acid to provide the title compound(±)-8. LCMS m/z 267 (MH+).

The following compounds were prepared by coupling 8D with an appropriateboronic acid or ester:

LCMS Cpd Structure (MH+) (±)-8E

265 (±)-8F

292 (±)-8G

266 (±)-8H

280 (±)-8I

266 (±)-8J

271 (±)-8K

313 (±)-8L

255 (±)-8M

269 (±)-8N

297 (±)-8P

283 (±)-8Q

297 (±)-8R

269 (±)-8S

284 (±)-8T

255 (±)-8U

316

Preparative Example 9

5-iodo-N-methylpyrimidin-4-amine (9A) was prepared from4-chloro-5-iodopyrimidine and methylamine as described in WO2008100456.Compound 9A (37.5 mg, 0.160 mmol.) was then mixed withbis(pinacolato)diboron (46.6 mmg, 0.184 mmol), KOAc (78.3 mg, 0.798mmol), and PdCl₂(dppf) (32.6 mg, 0.040 mmol) in dioxane (2.0 mL). Themixture was heated at 105° C. overnight in a 5 mL sealed tube and thencooled to RT. The reaction was then treated with compound 5D (22.59 mg,0.0800 mmol), K₂CO₃ (66.2 mg, 0.48 mmol), PdCl₂(dppf) (16.3 mg, 0.020mmol) and water (1.0 mL) and microwaved for 15 min at 125° C. Themixture was diluted with aq Na₂CO₃ and extracted with DCM. The organicextracts were dried over MgSO₄ and concentrated. Chromatography (0-10%of (9:1 MeOH/NH₃) in CH₂Cl₂) afforded (±)-9 (657 mg). LCMS m/z 312(MH+).

Preparative Example 10

A mixture of 4D (224 mg, 0.797 mmol), bis(pinacol)diboronate (405 mg,1.59 mmol), KOAc (313 mg, 2.39 mmol) and PdCl₂dppf.DCM (15 mg, 0.013mmol) in 1,4-dioxane (4.0 mL) was irradiated with microwaves for 15 minat 110° C. Then iodopyrimidine 9A (468 mg, 1.99 mmol) was added followedby sodium carbonate (338 mg, 3.19 mmol), 1,4-dioxane (2.0 mL) and water(4.0 mL). The resulting mixture was irradiated with microwaves for 15min at 130° C. The mixture was cooled to RT, diluted with water andextracted twice with DCM. The combined organic phase was dried overanhydrous Na₂SO₄ and the solvent removed in vacuo. The product waspurified by column chromatography (SiO₂, 10% MeOH(NH₃)/DCM) to give thetitle compound (±)-10 as a brown oily solid. LCMS m/z 310 (MH+).

In a similar manner, compound 4D was sequentially coupled withbis(pinacol)diboronate and 4,6-dimethyl-5-bromopyrimidine to providecompound (±)-10B. LCMS m/z 309 (MH+).

Preparative Example 11

A mixture of 4D (21 mg, 0.075 mmol), 3-tributyltin-pyridazine (83 mg,0.22 mmol) and PdCl₂dppf.DCM (15 mg, 0.013 mmol) in DMF (2.0 mL) wasirradiated with microwaves for 15 min at 130° C. The mixture wasextracted with DCM, washed with water and dried over anhydrous Na₂SO₄.The product was purified by column chromatography followed bypreparative TLC (SiO₂, 10% MeOH(NH₃)/DCM) to give (±)-11. LCMS m/z 281(MH+).

Preparative Example 12

The racemic mixture (±)-4B was separated on a preparative Chiralpak ADcolumn (SFC Chromatography with 20% MeOH-0.2% DEA) to provide the pureenantiomers 12A and 12B (>99% ee), which were separately advanced toprovide compound 12 (LCMS m/z 281/283, MH+) and compound 12C (LCMS m/z281/283, MH+), respectively, as described in Example 4.

Preparative Example 13

Step 1

LDA 2.0 M (0.62 mL, 1.14 mmol) was dropwise added to a solution ofsulfoxide 13A (J. Org. Chem. 1989, 54, 3130; 0.197 g, 1.039 mmol) in dryTHF (4 mL) at −75° C. under nitrogen. The mixture was stirred for 10 minand a solution of 7-bromo-2-tetrolone (242 mg, 1.044 mmol) in dry THF (2mL) was added dropwise over a period of 3 min. The resulting mixture wasstirred for 30 min at −75° C. and then TFA was added (0.40 mL). Themixture was warmed to RT, diluted with water, and extracted with DCM.The combined organic phase was dried and the solvent removed in vacuo togive an orange oil. Et₂O was added and the title compound 13Bprecipitated as a white solid (205 mg, 47%, 3:1 mixture ofdiastereomers).

Step 2

KOtBu (39 mg, 0.35 mmol) was added to a solution of a mixture ofdiastereomeric alcohols 13B (120 mg, 0.29 mmol) in a 1:1 mixture of drytBuOH and dry THF (20 mL) at RT. The resulting mixture was stirred for1.5 h and KOtBu (13 mg, 0.12 mmol) was added. The mixture was stirredfor another 30 min and the solvent evaporated. Water was added and themixture was extracted with DCM. The combined organic phase was dried andthe solvent removed in vacuo to give an orange oil which was purified bycolumn chromatography (AcOEt:hexanes 1% to 100%) to afford major epoxide13C (104 mg, 95% considering isolation of 16 mg of minor epoxide).

Step 3

Diphenylamino methane (0.185 mL, 1.06 mmol) was added to a solution ofepoxide 13C (80 mg, 0.212 mmol) in IPA (3 mL) at RT. The resultingmixture was heated at 90° C. for 17 h then cooled at RT. The solvent wasevaporated and the residue was purified by column chromatography (AcOEt:hexanes 1% to 10%) to afford the title compound 13D (38 mg, 43%) as apale brown glass.

Step 4

A solution of KOH (136 mg, 2.17 mmol) in dry MeOH (2 mL) was added to asolution of iodine (242 mg, 0.95 mmol) in dry MeOH (2 mL) and stirredfor 10 min. The resulting mixture was added to a solution of aldehyde13D (57 mg, 0.136 mmol) in MeOH (3 mL). The mixture was stirred for 25min, quenched with aq sat Na₂S₂O₃ and extracted with DCM. The combinedorganic phase was dried and the solvent evaporated in vacuo to give abrown glass that was purified by column chromatography (AcOEt: hexanes1% to 10%) to afford the title compound 13E (37 mg, 61%) as a colorlessglass.

Step 5

A solution of benzhydryl-protected aminoester 13E (37 mg, 0.082 mmol) intrifluoroacetic acid (3 mL) was heated in a 15 mL sealed tube at 90° C.for 1 h and 20 min. The mixture was cooled to RT, the solvent wasremoved and the residue quenched with NH₃ in MeOH solution (0.4 N). Thesolvent was evaporated and the residue was purified by columnchromatography (AcOEt: hexanes 1% to 100%) to afford the title compound12B (23 mg, 100%) as a pale brown glass.

Preparative Example 14

In a manner similar to that described in Example 2 (Step 1) and Example1 (Step 7), compound 1C was sequentially treated with CBzCl and thensubjected to a Suzuki reaction with pyrimidine-5-boronic acid to obtaincompound 14A and (±)-14. LCMS m/z 282 (MH+).

Compound (±)-14B was obtained in a similar fashion. LCMS m/z 311 (MH+).

Preparative Example 15

In a manner similar to Example 11, a mixture of compound 1E (40 mg,0.142 mmol), Pd(PPh₃)₄ (16.4 mg, 0.0142 mmol), KF (25 mg, 0.426 mmol),and 3-tributyltin-pyridazine (78.8 mg, 0.214 mmol) in dioxane (1.5 mL)was heated at 100° C. overnight. The mixture was cooled to RT andtreated with EtOAc (15 mL) and water (5 mL). The organic layer was dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (10% MeOH/DCM) to give compound(±)-15 as a white solid. LCMS m/z 281 (MH+).

The following compounds were prepared in a similar fashion:

Cpd Structure LCMS (MH+) (±)-15A

281 (±)-15B

281 (±)-15C

311

Preparative Example 16

Steps 1-2

In a manner similar to that described in Example 6 (Step 1),5-methoxy-2-tetralone was treated with ammonium carbonate and KCN.

A solution of the resulting hydantoin (7.02 g, 28.5 mmol) in DMF (80 mL)was treated with NBS (5.58 g, 31.4 mmol) at RT. The mixture was stirredfor 30 min and poured into water (200 mL). The slurry was filtered andwashed with water. The beige solid was dried in air to give 16A(quantitative yield).

Steps 3-8

Using the sequence described in Example 1 (Steps 2-7), 16A was convertedinto 16B and then coupled with pyrimidine-5-boronic acid under Suzukiconditions to provide the title compound (±)-16. LCMS m/z 311 (MH+).

The following compounds were prepared in an analogous fashion from 16B:

Cpd Structure LCMS (MH+) (±)-16C

309 (±)-16D

341 (±)-16E

328

Preparative Example 17

Compound 6A was brominated as described in Example 16 (Step 2) toprovide 17A, which was further advanced to compound 17D as previouslydescribed.

The following compounds were prepared from 17D by Suzuki coupling aspreviously described:

Cpd Structure LCMS (MH+) (±)-17

311 (±)-17E

327 (±)-17F

313

Preparative Example 18

To a stirred solution of (±)-16 (109 mg, 0.352 mmol) in CH₂Cl₂ (2.5 mL)was added BBr₃ (1M in DCM, 1.05 mL, 1.05 mmol) at 0° C. The mixture wasstirred at this temperature for 5 h and quenched with the addition ofsat. NaHCO₃ until pH 7. The mixture was extracted with EtOAc (50 mL),dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresidue was purified by column chromatography (10% MeOH/CH₂Cl₂, 1%NH₄OH) to give compound (±)-18 as a white solid. LCMS m/z 297 (MH+).

Compound (±)-18A (LCMS m/z 297, MH+) was prepared from (±)-17 in asimilar fashion.

Preparative Example 19

To a solution of compound 19A (prepared from 16B and BBr₃ as previouslydescribed in Example 18, 640 mg, 1.6 mmol) in THF (10 mL) was addedPhNTf₂ (571.6 mg, 1.6 mmol) and TEA (0.556 mL, 4 mmol) at RT. Thereaction mixture was stirred overnight and concentrated under reducedpressure. The crude was purified with column chromatography (10%MeOH/DCM) to give compound 19B as a white foam. Suzuki reaction of 19Bproduced compound (±)-19 as a clear glass. LCMS m/z 429 (MH+).

Preparative Example 20

Step 1

In a manner similar to that described in Example 2 (Step 1), (±)-7B wasprotected with Boc₂O to provide (±)-20A as the major product and (±)-20B(LCMS m/z 381, MH+) as the minor product.

Steps 2-3

To a solution of (±)-20B (40.8 mg, 0.107 mmol) in THF (1 mL) was addedMeI (0.02 mL, 0.321 mmol) and NaH (60% dispersion in mineral oil, 6.4mg, 0.16 mmol) at RT. The mixture was stirred for 1 hr before it wasquenched with the addition of water and extracted with EtOAc. Theorganic layer was dried (Na₂SO₄), filtered and concentrated to give thecrude product (30.6 mg).

The crude material was dissolved in DCM (1 mL) and treated with TFA (1mL) at RT. After 2 hr, the mixture was concentrated under reducedpressure and purified using column chromatography (10% MeOH/DCM) to givethe title compound (±)-20 as a white foam (11.2 mg, 50%). LCMS m/z 295(MH+).

Compound (±)-20C (LCMS m/z 295, MH+) was prepared from compound 1 in asimilar fashion.

Preparative Example 21

In a manner similar to that described previously (Example 1),5-bromo-2-tetralone was converted into the amino ester (±)-21A. Theracemic mixture was then separated on a preparative Chiralpak OD column(30% EtOH-hexanes with 0.2% DEA) to provide the pure enantiomers 21B and21C (>95% ee).

Alternatively, 21B and 21C were synthesized by an asymmetric approachoutlined below:

Step 1

A mixture of 5-bromo-2-tetralone (2.0 g, 8.89 mmol), (R)-phenylglycinol(1.22 g, 8.89 mmol, 1.0 eq), and 4 Å molecular sieves in CHCl₃ (50 mL)was refluxed until the starting material disappeared (monitored by ¹HNMR). After filtering the molecular sieves the solvent was removed underreduced pressure, the residual oil 21D was used for the next stepwithout further purification.

Step 2

To a solution of 21D in 10 mL CH₂Cl₂ at 0° C. was added TMSCN (1.67 mL,13.34 mmol, 1.5 eq) followed by MeOH (3.5 mL). The cooling bath wasremoved and the reaction mixture was stirred at RT for 24 h. Thesolution was concentrated at reduced pressure and the residue 21E wasused for the next step without any purification.

Step 3

The oily residue 21E was dissolved in 10 mL MeOH and cooled in anice-water bath. Anhydrous HCl (g) was bubbled through the solution untilsaturation. After stirring for 1 h, the MeOH was evaporated and theresidue was diluted with 100 mL of EtOAc. The organic layer was washedwith 10% aq NaHCO₃, brine and dried over Na₂SO₄. After removal of thesolvent, the amino ester was purified by SFC chromatography to yield 21F(1.75 g) and 21G (0.43 g).

Step 4

To a solution of 21F (330 mg, 0.82 mmol) in DCM (3.5 mL) and MeOH (1.8mL) was added lead tetraacetate (362 mg, 0.82 mmol, 1.0 eq) at 0° C.After the resultant mixture was stirred for 30 min, 10 mL of phosphatebuffer (pH 7) was added to quench the reaction. The mixture was filteredthrough celite, and the organic layer was separated, washed with water,and concentrated to dryness. The residual oil was purified by flashchromatography (1% MeOH/CH₂Cl₂) to yield 111 mg of the R— amino ester21C.

In a manner similar to that described previously (Examples 1 and 3), theindividual enantiomers 21B and 21C were subjected to the followingsequence to provide compounds listed in the table below: reduction withNaBH₄, cyclization with BrCN, and Suzuki coupling with the appropriateboronic acid or boronic ester.

Cpd Structure LCMS (MH+) 21H

285 211

269 21J

283 21K

280 21L

285 21M

269 21N

283 21O

280

Preparative Example 22

Steps 1-3

To a stirred solution of 17C (1.53 g, 5.33 mmol) in THF (20 mL) wasadded EtOCONCS (0.7 g, 5.33 mmol). The mixture was stirred at RT for 2 hand concentrated under reduced pressure. The residue was dissolved inEtOH (40 mL) and then treated with Hg(OAc)₂ (1.698 g, 5.33 mmol) in oneportion. After stirred for 2 h, the dark suspension was filtered througha pad of celite and concentrated under reduced pressure. The crudematerial was purified by column chromatography (55% hexanes/EtOAc) togive 22A. This material was separated by Chiralpak AD HPLC (12%IPA/hexanes) to give compound 22B (LCMS m/z 383, MH+) and 22C (LCMS m/z383, MH+) as white solid (total 1.02 g, 50%).

Steps 4-5

Employing previously described procedures for the Suzuki reaction(microwave, 110° C., 15 min), compound 22D was prepared from 22C.

To a solution of 22D (25 mg, 0.065 mmol) in MeOH/water (1:1, 3 mL) wasadded LiOH (27.3 mg, 0.65 mmol). The mixture was refluxed for 2 hr andconcentrated under reduced pressure to remove MeOH. The residue wasextracted with EtOAc and dried (Na₂SO₄), filtered, and concentratedunder reduce pressure. The crude material was purified by columnchromatography (10% MeOH/DCM) to give compound 22 as a white solid (14.1mg, 70%). LCMS m/z 311 (MH+).

In a similar manner, compound 22E was prepared from 22B. LCMS m/z 311(MH+).

Compounds 22F (LCMS m/z 297, MH+) was prepared from 22 in a mannersimilar to that described in Example 18. Likewise, compound 22G (LCMSm/z 297, MH+) was prepared from 22E.

Preparative Example 23

In a manner similar to that previously described, compound (±)-22A wassequentially subjected to Suzuki conditions with pyrimidine-5-boronicacid, treated with BBr₃, and reacted with Tf₂O to provide (±)-23B.

A solution of (±)-23B (14.3 mg, 0.0336 mmol) in dixane (1 mL) wastreated with Pd(PPh₃)₄ (4 mg, 0.0034 mmol), vinyltributyl tin (0.020 mL,0.0672 mmol), and LiCl (4.3 mg, 0.101 mmol). After being stirred at 100°C. overnight, the mixture was cooled and treated with EtOAc (5 mL) andwater (2 mL). The organic layer was separated, dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The crude material was purifiedby prep-HPLC (0-50% CH₃CN/H₂O) to give compound (±)-23 as a clear glass(2.0 mg, 20%). LCMS m/z 307 (MH+).

Compounds (±)-23C (LCMS m/z 359, MH+) and (±)-23D (LCMS m/z 267, MH+)were synthesized using a similar approach (Suzuki reaction in the finalstep):

Preparative Example 24

Step 1

In a manner similar to that described in Example 6 (Step 5), compound 6Cwas treated with Boc₂O. To a solution of the resulting product (1.767 g,5.756 mmol) in CH₂Cl₂ (30 mL) was added Dess-Martin periodinate (3.66 g,8.634 mmol) at RT. The mixture was stirred for 1 h and quenched withaddition of NaS₂O₅ solution (1 M, 20 mL). The organic layer wasseparated and washed with saturated NaHCO₃ solution and brine. Theorganic phase was dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The crude material was purified by columnchromatography (15% EtOA/hexanes) to give aldehyde 24A as a white solid(1.637 g, 95%).

Step 2

To a solution of compound 24A (1.673 g, 5.485 mmol) in CH₂Cl₂ (30 mL)was added MeMgBr (3 M solution in THF, 4.2 mL, 12.6 mmol) at −78° C. Themixture was stirred at this temperature for 1 h and quenched withaddition of saturated NH₄Cl solution (20 mL) and EtOAc (80 mL). Theorganic layer was separated, washed with brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude material(white solid, 1.756 g, 97%) was deprotected with TFA in a manner similarto that described in Example 3 (Step 3) to provide 24B.

Step 3

In a manner similar to that previously described, compound 24B wascyclized (Example 22, Steps 1-2), brominated (Example 16, Step 2),coupled with the 5-pyrimidine-5-boronic acid (Example 1, Step 7), anddeprotected (Example 22, Step 5) to give compound (±)-24. LCMS m/z 325(MH+).

Separation of 24E (Chiralpak AD, SFC Prep-HPLC) followed by deprotectionprovided the four pure diastereomers 24F (LCMS m/z 325, MH+), 24G(LCMSm/z 325, MH+), 24H(LCMS m/z 325, MH+), and 241(LCMS m/z 325, MH+).

Preparative Example 25

Steps 1-3

A mixture of 5-bromotetralone (5.5 g, 24.4 mmol) and pyrrolidine (2.6 g,36.6 mmol) in toluene (100 mL) was heated at reflux with a Dean Starktrap for 48 h. The reaction was then concentrated to give 25A as a darkfoam. LCMS m/z 278/280 (MH+).

The enamine 25A was dissolved in 100 mL of 1,4-dioxane, tread with 15 mLof MeI and heated at reflux overnight. The reaction was cooled down inan ice bath and then treated with 40 mL H₂O and 1.5 mL AcOH. Afterheating at reflux for 3 h, the reaction was concentrated andchromatographed (5% to 15% ether/hexanes) to give a light yellow oil 25B(2.85 g, 49% for 2 steps).

Steps 4-10

In a manner similar to that described in Example 1, compound 25B wasadvanced to 25D (LCMS m/z 295/297, MH+). Final Suzuki coupling withpyrimidine-5-boronic acid provided the title compound (±)-25 as amixture of 4 stereoisomers. LCMS m/z 295 (MH+).

The four stereoisomers of compound 25 were separated first by semi-prepAD column (10% EtOH/Hex with 0.1% DEA) to give a mixture of 25E and 25Fand pure samples of 25G and 25H. The mixture of 25E and 25F wasseparated by semi-prep OJ (10% EtOH/Hex with 0.1% DEA) to give puresamples of 25E and 25F.

Preparative Example 26

In a manner similar to that described in Example 1, 21A was reduced withNaBD₄ and then cyclized with PhC(O)NCS. Chiral separation, hydrolysisand Suzuki coupling provided the S-enantiomer 26. LCMS m/z 283 (MH+).Likewise, the R-enantiomer 26D was also synthesized. LCMS m/z 283 (MH+).

Preparative Example 27

A solution of compound 21A (0.92 g, 3.24 mmol) in THF (15 mL) wastreated slowly with MeMgBr (6 mL of a 3.0M solution/Et₂O) and thenstirred overnight at RT. The reaction was cooled in an ice bath,quenched with sat. aq. NH₄Cl, and stirred for 30 min. The mixture wasthen treated with 1.0 M NaOH (˜10 mL) and then extracted with DCM (3×),dried over Na₂SO₄, and concentrated to give 27A as a brown foam (0.92g).

In a manner similar to that described in Example 22, 27A was cyclizedwith PhC(O)NCS/Hg(OAc)₂, hydrolyzed and coupled withpyrimidine-5-boronic acid to provide the title compound (±)-27. LCMS m/z309 (MH+). The pure enantiomers 27D (LCMS m/z 309, MH+) and 27E (LCMSm/z 309, MH+) were separated by chiral HPLC (AD column, 10% EtOH-hexaneswith 0.1% DEA).

Preparative Example 28

Steps 1-5

8-Bromochroman-3-one 28B was prepared from 2-bromophenol in a mannersimilar to that described in the literature (J. Med. Chem., 1988, 689):Reaction of 2-bromophenol with paraformadehyde (MgCl₂, NEt₃, THF, 75°C., 4 h), followed by treatment with acrylonitrile (neat, Dabco, 95° C.,18 h), and hydrolysis with 10% NaOH (100° C., 4 h) afforded 28A.Compound 28A was reacted with DPPA (NEt₃, toluene, 110° C., 2 h)followed by treatment with 6N HCl (85° C., 2 h) to afford8-bromochroman-3-one 28B.

Steps 6-11

Compound 28D was prepared from 28B in a manner similar to that describedin Example 1: hydantoin formation with (NH₄)₂CO₃/KCN, hydrolysis withLiOH, methyl ester formation with SOCl₂/MeOH, and reduction with NaBH₄.The reaction of compound 28D with cyanogen bromide provided 28E (THF,RT, 3 h, in a manner similar to that described in Example 3, Step 4).The title compound (±)-28 was prepared from 28E via Suzuki coupling withpyrimidine-5-boronic acid/Pd(dppf)Cl₂ in a manner similar to thatdescribed in Example 1 (Step 7). LCMS m/z 283 (MH+).

The racemic mixture (±)-28 was separated on a preparative Chiralpak ADcolumn with 10% EtOH-hexanes to provide the pure enantiomers (R)-28F(LCMS m/z 283, MH+) and (S)-28G (LCMS m/z 283, MH+).

Preparative Example 29

Compound 28E (20 mg, 0.07 mmol), 2-(tributylstannyl)pyrazine (41 mg,0.11 mmol), Pd(PPh₃)₄ (8 mg, 0.007 mmol) and KF (12 mg, 0.21 mmol) wereplaced in a microwave reactor and sealed. The inside air was exchangedwith N₂. Dioxane was added (2.0 mL) and the reaction was heated at 120°C. in an oil bath for 20 h. The reaction was concentrated and purified(silica, CH₂Cl₂ with 1-4% 7N NH₃-MeOH) to provide compound (±)-29 (11mg, 55%) as pale yellow solid. LCMS m/z 283 (MH+).

Compound (±)-29A was prepared from 28E in a manner similar to thatdescribed as above (coupling with 4-(tributylstannyl)thiazole). LCMS m/z288 (MH+).

Preparative Example 30

Compound 30A was prepared by the Boc protection of the amino group incompound 28D with Boc₂O (NEt₃, THF, RT, overnight) followed by oxidationof hydroxymethyl group with Dess-Martin periodinane (CH₂Cl₂, RT, 30 min)in a manner similar to that described in Example 24 (Step 1). Subsequentreaction with MeMgBr (CH₂Cl₂, RT, 30 min) in a manner similar to thatdescribed in Example 24 (Step 2) provided compound 30B. deprotection of30B (1:5 TFA-CH₂Cl₂, RT, 4 h) was followed by reaction with EtOC(O)NCS(THF, RT, 40 min), cyclization with Hg(OAc)₂ (EtOH, RT, 2 h) andtreatment with LiOH (MeOH—H₂O, 2:1, 100° C., 3 h) in a manner similar tothat previously described. The compound (±)-30 was prepared by Suzukicoupling of compound 30C with pyrimidine-5-boronic acid/Pd(dppf)Cl₂ in amanner similar to that described in Example 1 (Step 7). LCMS m/z 297(MH+).

The racemic mixture (±)-30 was further purified on a preparativeChiralpak AD column (15% IPA-hexanes) to provide the pure enantiomers30D (LCMS m/z 297, MH+), 30E (LCMS m/z 297, MH+) and a mixture of twoisomers. This mixture could be separated on a preparative Chiralpak ODcolumn (10% EtOH-hexanes) to provide the pure enantiomers 30F (LCMS m/z297, MH+) and 30G (LCMS m/z 297, MH+).

Preparative Example 31

In a manner similar to Example 1 (Steps 1 and 7), 5-bromo-2-tetralonewas converted to 31B. LCMS m/z 295 (MH+).

A solution of crude 31B (0.5 g, 1.7 mmol) in DMF (5 mL) was treated withKHCO₃ (0.48 g, 4.76 mmol) and 4-methoxybenzyl chloride (0.53 mL, 3.91mmol). After stirring at 60° C. for 20 h, the mixture was extracted withEtOAc and brine, dried over Na₂SO₄, concentrated and purified to give31C (0.1 g).

Compound 31C (0.045 g) was suspended in POCl₃ (1.5 mL) and heated at170° C. in a microwave reactor for 1.5 h. The reaction was thenconcentrated, dissolved in NH₃/MeOH (10 mL, 7N), transferred to a sealedtube, and heated at 85° C. for 20 h. The solvent was removed; theproducts were purified by reverse-phase HPLC to afforded 31D (0.009 g,LCMS m/z 414, MH+), (±)-31 (0.002 g, LCMS m/z 294, MH+), and 31C (0.025g, LCMS m/z 415, MH+).

In a similar fashion, compound (±)-31G was synthesized:

A solution of crude compound 31A (0.2 g, 0.68 mmol) in DMF (5 mL) wastreated with CsHCO₃ (0.26 g, 1.36 mmol) and MeI (0.17 mL, 2.72 mmol).After stirring at RT for 20 h, the mixture was extracted with EtOAc andbrine, dried over Na₂SO₄, concentrated and purified by silica gelchromatography to give (±)-31E (0.07 g). In a manner similar to thatdescribed in Example 1 (Step 7), compound 31E was subjected to Suzukicoupling with pyrimidine-5-boronic acid to provide (±)-31F (LCMS m/z309, MH+). Treatment with POCl₃/NH₃ as described earlier in this exampleprovided (±)-31G. LCMS m/z 308, (MH+).

Preparative Example 32

Step 1

A solution of 5-bromo-2-tetralone (1.5 g, 6.66 mmol) in a 1:1 mixture ofEtOH/H₂O (50 mL) was treated with KCN (1.3 g, 19.99 mmol, 3.0 eq) andNH₄Cl (1.78 g, 33.3 mmol, 5.0 eq). The reaction mixture was heated to60° C. for 16 h after which it cooled to RT. Saturated NaHCO₃ (40 mL)was added and extracted with CH₂Cl₂ (3×50 mL). The combined organiclayer was dried over Na₂SO₄, filtered, and concentrated to yield crude32A which was carried to the next step without purification.

Step 2

A solution of the crude amino nitrile 32A in HCO₂H (20 mL) was cooled to0° C. and saturated with anhydrous HCl (g). After 10 min, the excessformic acid was evaporated and the residue was taken up in acetone (25mL). Filtration of the white solid afforded compound 32B (1.25 g).

Step 3

To a suspension of compound 32B (500 mg, 1.86 mmol) in CH₂Cl₂ (10 mL)was added Et₃N (0.52 mL, 3.72 mmol, 2.0 eq). Acetyl chloride (0.16 mL,2.23 mmol, 1.2 eq) was slowly added and the reaction was left to stir atRT overnight. After the reaction was complete, aq. NaHCO₃ (15 mL) wasadded. Extraction with CH₂Cl₂ (2×20 mL), drying over Na₂SO₄, andevaporation under reduced pressure gave a crude mixture which waspurified by flash chromatography using a gradient of DCM/MeOH (98/2) toyield 32C (525 mg). LCMS m/z 293/295 (MH+).

Step 4

A mixture of 32C (100 mg, 0.34 mmol), pyrimidine-5-boronic acidhemihydrate (82 mg, 0.61 mmol, 1.8 eq), PdCl₂(PPh₃)₂ (24 mg, 0.034 mmol,10 mol %) and Na₂CO₃ (108 mg, 1.025 mmol, 3 eq) in 3.0 mL of DME/H₂O(4:1) was heated to 120° C. for 20 min in a microwave. After cooling,the reaction mixture was loaded onto a flash column and purified byeluting with 1% to 3% MeOH/CH₂Cl₂ to yield 75 mg of (±)-32 as a whitepowder. LCMS m/z 293 (MH+).

Preparative Example 33

A solution of 32B (100 mg, 0.37 mmol) and trimethyl orthoformate (0.049mL, 0.44 mmol, 1.2 eq) in 1 mL DMF was microwaved at 140° C. for 40 min.Upon cooling, H₂O (5 mL) was added and the mixture was extracted withEtOAc (2×10 mL), dried over Na₂SO₄, filtered, and evaporated underreduced pressure. The crude product was purified by flash chromatographyby eluting with 2-4% MeOH/CH₂Cl₂ to yield 30 mg of compound (±)-33. LCMSm/z 279/281 (MH+).

In a manner similar to that described in Example (Step 7), (±)-33 iscoupled with pyrimidine-5-boronic acid to give (±)-33A.

Preparative Example 34

In a manner similar to that previously described, compound (±)-34 (LCMSm/z 281/283, MH+) was synthesized from 6-bromo-2-tetralone. Thefollowing compounds were prepared from (±)-34 following proceduressimilar to those exemplified in the examples above:

LCMS Cpd Structure (MH+) (±)-34A

281 34B

281 34C

281 (±)-34D

279 (±)-34E

280 (±)-34F

296 (±)-34G

268 (±)-34G

283 (±)-34I

280 (±)-34J

311 (±)-34K

297 34L

297 34M

297 (±)-34N

298 34O

281/283 34P

281/283

Preparative Example 35

Steps 1-3

In a manner similar to that described in Example 21, 5-bromo-2-tetralonewas sequentially treated with (S)-phenylglycinol, TMSCN and HCl (g)-MeOHto provide 35A.

Steps 4-5

A mixture of 35A (3.0 g, 7.42 mmol), acetone dimethyl acetal (22.7 mL,185.5 mmol, 25.0 equiv), and p-toluenesulfonic acid (71 mg, 0.37 mmol,0.05 equiv) in C₆H₆ (10 mL) was refluxed in the presence of 4 Åmolecular sieves for 12 h. After cooling, the molecular sieves werefiltered, the solvent was removed under reduced pressure, and theresidual oil was purified by flash chromatography (5% EtOAc/hexanes, 1.8g product).

n-Butyllithium (23.1 mL, 36.96 mmol, 10.0 equiv, 1.6 M in hexanes) wasadded dropwise to a solution of N,O-dimethylhydroxylamine-HCl (1.8 g,18.48 mmol, 5.0 equiv) in THF (50 mL) at −78° C. The cooling bath wasremoved and the reaction was stirred at RT for a period of 30 minutes. Asolution of the product from the previous step (1.76 g, 3.7 mmol) in 10mL THF was added dropwise to the reaction mixture at −78° C. After 1 hof stirring at −78° C., sat. NH₄Cl (30 mL) was added to the reactionmixture and warmed to RT. The mixture was extracted with EtOAc (2×25mL), washed with brine and dried over Na₂SO₄. After concentration, thecrude mixture was purified by flash chromatography (10-20%EtOAc/hexanes) to yield 1.8 g of 35B.

Steps 6-7

DIBAL-H (7.5 mL, 7.5 mmol, 2.1 equiv, 1.0 M in hexanes) was addeddropwise to a solution of 35B (1.8 g, 3.58 mmol) in THF (25 mL) at −78°C. After 1 h of stirring, the reaction was quenched by the addition ofsat. NH₄Cl (10 mL). The reaction mixture was extracted with EtOAc (2×20mL), washed with brine and dried over Na₂SO₄. After concentration, thecrude reaction mixture was purified by flash chromatography (10%EtOAc/hexanes, 1.5 g product).

Ethylmagnesium bromide (1.57 mL, 4.7 mmol, 2.1 equiv, 3.0 M in Et₂O) wasadded dropwise to a solution of the product from the previous step (1.0g, 2.24 mmol) in CH₂Cl₂ (15 mL) at −78° C. After stirring at −78° C. for1.5 h, the reaction was quenched by the addition of sat. NH₄Cl (5 mL).The organic layer was separated and the aqueous layer was extracted withCH₂Cl₂ (2×10 mL). The combined organic layers were washed with 4 N HCl(20 mL), neutralized with sat. NaHCO₃ and extracted with CH₂Cl₂ (2×20mL). The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. The crude alcohol was purified by flash chromatography (5%MeOH/CH₂Cl₂) to yield 700 mg of 35C as a white solid.

Steps 8-9

A mixture of 35C (200 mg, 0.49 mmol), 2-methylpyridine-3-boronic acid(101 mg, 0.74 mmol, 1.8 equiv), PdCl₂(PPh₃)₂ (34 mg, 0.049 mmol, 10 mol%) and Na₂CO₃ (156 mg, 1.47 mmol, 3 equiv) in 3.0 mL of DME/H₂O (4:1)was heated to 120° C. for 20 min in a microwave. After cooling, thereaction mixture was chromatographed (1-3% MeOH/CH₂Cl₂ to yield thedesired product (190 mg) as an off white powder.

To a solution of the product (184 mg, 0.44 mmol) in 10 mL MeOH was addedPd(OH)₂ (310 mg, 0.44 mmol). The reaction mixture was hydrogenated at 40psi using a Parr shaker for 24 h after which it was filtered throughcelite and concentrated. The crude product was purified by flashchromatography (20% MeOH/DCM) to yield 43 mg of the desired product 35D.

Step 10

To a solution of 35D (40 mg, 0.14 mmol) in 5 mL CH₃CN was added TEA (31μL, 0.21 mmol, 1.5 equiv) followed by BrCN (36 μL, 0.18 mmol, 1.25equiv, 5 M in CH₃CN). The reaction was stirred at RT overnight afterwhich 10 mL of water was added, extracted with EtOAc (2×10 mL), driedover Na₂SO₄ and concentrated. The crude product was purified by flashchromatography (10% MeOH/DCM) to yield 12 mg of the desired product 35.LCMS m/z 322 (MH+).

Preparative Example 36

In a manner similar to that previously described, a solution of compound4C is treated with EtOC(O)NCS (1.2 eq) in THF, stirred for 3 h at RT,and then concentrated to provide 36A.

Crude compound 36A is taken up in CH₃CN, cooled in an ice bath, andtreated with 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (1.2 eq)portionwise. The reaction is stirred for 1.5 h and then sequentiallyquenched with TEA and water. The mixture is extracted with DCM (2×) andconcentrated to provide 36B.

Compound 36B is then deprotected with LiOH in a manner similar to thatpreviously described to provide 4D.

Preparative Example 37

Step 1

A 3-neck round bottom flask fitted with a condenser was charged withAlCl₃ (41.6 g, 0.31 mol) and then heated to 75° C. 1-Benzosuberone (20g, 0.13 mol) was added dropwise to the hot AlCl₃. To the resulting brownslurry was added Br₂ (24 g, 0.15 mol) dropwise. The reaction mixture wasstirred for 5 min before it was cooled to 0° C. The reaction mixture wasquenched with ice chips. Concentrated HCl was added slowing withstirring to get the mixture into solution. The mixture was diluted withH₂O and extracted the organic layer with Et₂O (2×). The combined organiclayers were dried (MgSO₄), filtered and concentrated under reducedpressure to give a mixture of 6-bromocyclohepta-1-one 37A and8-bromocyclohepta-1-one 37B (in a 1:2 ratio)

Step 2

To a 1:2 mixture of 37A and 37B in MeOH (20 mL) and THF (40 mL) wasadded NaBH₄ at 0° C. The reaction mixture was stirred at RT for 1 h,neutralized with 1N HCl, diluted with H₂O and extracted the organiclayer with Et₂O. The combined organic layers were dried (MgSO₄),filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (5-10% EtOAc/Hexanes) to give1-hydroxy-8-bromo-benzocycloheptane 37C (9.1 g) and1-hydroxy-6-bromo-benzocycloheptane 37D (19.7 g).

Step 3

To a solution of 37C (4.4 g, 0.02 mol) in toluene (50 mL) was addedmolecular sieves and p-toluenesulfonic acid monohydrate (347 mg, 1.82mmol). The reaction mixture was refluxed for 3 h, cooled to RT, quenchedwith sat. NaHCO₃ solution and extracted with CH₂Cl₂ (2×). The combinedorganic layers were dried (MgSO₄), filtered and concentrated underreduced pressure to give the alkene 37E (used directly in next step).

Step 4

To a solution of 37E in toluene (50 mL) was added mCPBA (4.4 g, 0.03mol) in 3 portions. The reaction mixture was stirred at RT for 1 h,quenched with aq sodium sulfite (10%), extracted with CH₂Cl₂. Theorganic layer was washed with 1N NaOH, dried (MgSO₄), filtered andconcentrated under reduced pressure to give the epoxide 37F (useddirectly in next step).

Step 5

To a solution of 37F in toluene (50 mL) was added ZnI₂ (7.31 g, 0.02mol) at 0° C. The reaction mixture was stirred at RT for 1.5 h, dilutedwith H₂O. The mixture was extracted with CH₂Cl₂. The combined organiclayer was dried (MgSO₄), filtered and concentrated under reducedpressure. Flash chromatography (EtOAc/Hexanes, 1:9) afforded the desiredproduct 37G (2.3 g, 53%).

Steps 6-10

In a manner similar to that described previously (Example 1, Steps 1-4and Example 3, Step 4), compound 37G was subjected to the followingsequence: hydantoin formation with (NH₄)₂CO₃/KCN, hydrolysis with LiOH,methyl ester formation with SOCl₂/MeOH, reduction with NaBH₄, andcyclization with BrCN to provide (±)-37H (LCMS m/z 295/297, MH+). FinalSuzuki coupling with pyrimidine-5-boronic acid afforded the titlecompound (±)-37. LCMS m/z 295 (MH+).

The racemic mixture (±)-37 was separated on a preparative Chiralpak ODcolumn with 20% IPA-hexanes (with 0.5% DEA additive at 10 mL/min) toprovide the pure enantiomers 371 (LCMS m/z 295, MH+) and 37J (LCMS m/z295, MH+).

Compounds 37K, (±)-37L (LCMS m/z 295/297, MH+), and (±)-37M (LCMS m/z295, MH+) were synthesized from 37D in a similar manner:

The racemic mixture (±)-37M was separated on a preparative Chiralpak ADcolumn with 18% IPA-hexanes (with 0.5% DEA additive at 10 mL/min) toprovide the pure enantiomers 37N (LCMS m/z 295, MH+) and 37M (LCMS m/z295, MH+).

Preparative Example 38

Steps 1-2

To an ice cooled solution of KOtBu (1.0M in THF, 42 mL, 0.042 mol) inEt₂O was added a solution of 5-bromo-1-teralone (9.0 g, 0.04 mol) inEt₂O (50 mL) dropwise, followed by a solution of BuONO (4.94 g, 0.048mol) in Et₂O (20 mL). The mixture was stirred at RT for 30 min,acidified with 1N HCl, and diluted with DCM. The organic layer was dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas dissolved in HOAc (30 mL) and Ac₂O (20 mL). Zn powder (7.8 g, 0.12mol) was added in 3 portions. The mixture was stirred at RT for 1 h, andthen filtered. The filtrate was concentrated in vacuo. Flashchromatography (EtOAc/Hexanes, 1:2 then 2:1) afforded the product 38A(5.0 g).

Step 3

To a solution of 38A (5.0 g, 0.018 mol) in EtOH (50 mL) and H₂O (8 mL)was added formaldehyde (37% in H₂O, 6 mL) and K₂CO₃ (1.23 g, 0.009 mol).The mixture was stirred at RT for 18 h, and then diluted with DCM. Theorganic phase was dried (MgSO₄), filtered and concentrated in vacuo.Flash chromatography (EtOAc/Hexanes, 1:2 then 2:1) afforded the alcohol38B (5.0 g).

Step 4

A mixture of 38B (5 g) in 1N HCl (150 mL) was refluxed for 1.5 h andthen cooled to RT. The mixture was concentrated in vacuo. Flashchromatography (MeOH (7N NH₃)/Hexanes, 1:10) afforded the alcohol 38C(3.1 g).

Steps 5-6

In a manner similar to that previously described (Example 3, Step 4),compound 38C was cyclized with BrCN to provide 38D. LCMS m/z 295/297(MH+). Final Suzuki coupling with pyrimidine-5-boronic acid afforded thetitle compound (±)-38. LCMS m/z 295 (MH+).

The racemic mixture (±)-38 was separated on a preparative Chiralpak ODcolumn with 14% IPA-hexanes (with 0.5% DEA additive at 10 mL/min) toprovide the pure enantiomers 38E (LCMS m/z 295, MH+) and 38F (LCMS m/z295, MH+).

Reduction of 38E (3 eq. NaHB(OAc)₃ then 3 eq. NaBH₄ in 1:1 MeOH-DCM)followed by chromatographic separation (prep TLC with 10% of 7N NH₃-MeOHin DCM) provided the stereoisomers 38G (LCMS m/z 297, MH+) and 38H (LCMSm/z 297, MH+). Similar treatment of 38F provided 381 (LCMS m/z 297, MH+)and 38J (LCMS m/z 297, MH+). Likewise, treatment of 38D provided (±)-38Kas a mixture of stereoisomers. (LCMS m/z 297/299, MH+).

Preparative Example 39

To a solution of KOtBu (13.2 g, 0.12 mol) in Et₂O (100 mL) at 0° C., wasadded the mixture of 37A and 37B (26.7 g, 0.11 mol) in Et₂O (250 mL)slowly, followed by n-butyl nitrite (13.8 g, 0.13 mol). The reactionmixture was stirred at RT for 30 min, diluted with H₂O, acidified to pH3 with 1N HCl, and then extracted with CH₂Cl₂. The combined organiclayers were dried (MgSO₄), filtered and concentrated in vacuo.

The crude residue was dissolved in AcOH (30 mL) and Ac₂O (25 mL) at 0°C. Zn powder (36.0 g, 0.55 mol) was added to reaction mixture inportions. The reaction mixture was stirred at RT for 1 h, filteredthrough a pad of celite, washing with CH₂Cl₂. The filtrate wasconcentrated in vacuo. Flash chromatography (EtOAc/Hexanes, 2:1)provided 39A (6 g) and 39B (6.7 g).

In a manner similar to that described in Example 38, the followingcompounds were synthesized from 39A and 39B.

Cpd Structure LCMS (MH+) (±)-39C

309/311 (±)-39D

309 39E

309 39F

309 (±)-39G

309/311 (±)-39H

309 (±)-39I

311

Preparative Example 40

In a manner similar to that described in Example 38, the compounds weresynthesized from the appropriate bromo-2-tetralone.

Cpd Structure SM LCMS (MH+) (±)-40A

295/297 (±)-40B

295 (±)-40C

295/297 (±)-40D

295

Preparative Example 41

Steps 1-2

In a sealed tube 5-bromo-2-tetralone (2.00 g, 8.88 mmol) was dissolvedin EtOH (40.0 mL, 685 mmol) and Water (33.0 mL, 1830 mmol). KCN (1.157g, 17.77 mmol) followed by NH₄Cl (1.901 g, 35.54 mmol) were added. Thereaction was heated to 60° C. and stirred overnight. The mixture wasdiluted with DCM and sat. NaHCO₃. The biphasic solution was separatedand the aqueous layer was extracted with DCM in three portions. Thecombined organic phase was dried over anhydrous sodium sulfate andconcentrated to dryness to provide 41A (2.3 g, 100%).

A solution of 41A (2.20 g, 8.76 mmol) in THF (20.0 mL, 246 mmol) wastreated with LAH (2.0 M/THF, 6.57 mL) and stirred at RT for 30 min. Thereaction was cooled in an ice/water bath and slowly quenched with water(dropwise) followed by 10% NaOH. The mixture was warmed to RT andstirred for 3 h. The material was filtered through celite, washed with asolution of 1:1 MeOH/DCM in three portions and concentrated to drynessto provide 41B (2.14 g, 96%).

Steps 3-4

A mixture of 41B (200 mg, 0.78 mmol) and formamidine acetate (106 mg,1.02 mmol) in EtOH (10 mL, 171 mmol) under Ar was stirred for 1 h at RT.The mixture was diluted with DCM and sat. sodium bicarbonate. Thebiphasic solution was separated and the aqueous layer was extracted withDCM in three portions. The combined organic phase was dried overanhydrous sodium sulfate and concentrated to provide (±)-41C (201 mg,97%). LCMS m/z 265/267 (MH+).

In a manner to that described in Example 1 (Step 7), 41C was coupledwith pyrimidine-5-boronic acid to provide the title compound (±)-41.LCMS m/z 265 (MH+).

The following compounds were synthesized by coupling with 41C aspreviously described.

Cpd Structure LCMS (MH+) (±)-41D

263 (±)-41E

267 (±)-41F

253 (±)-41G

269 (±)-41H

269Steps 5-6

Alternatively, compound 41B was synthesized from 21A by the followingtwo-step procedure:

A solution of 21A (190 mg, 0.67 mmol) in NH₃-MeOH (7N, 12 mL) was heatedto 105° C. overnight in a sealed tube. The reaction mixture wasconcentrated to provide 41I (191 mg, 106%).

A solution of compound 41I (180 mg, 0.67 mmol) in THF (10 mL) in asealed tube was treated slowly with BH₃—SMe₂ (2M/THF, 1 mL). Thereaction mixture was heated to 105° C. for 2 h, then cooled to 0° C. inan ice/water bath and quenched with EtOH followed by K₂CO₃. The mixturewas warmed to RT and stirred for 2 h. The material was filtered throughcelite, washed with EtOH in three portions and concentrated. The crudemixture was diluted with DCM and sat. sodium bicarbonate. The biphasicsolution was separated and the aqueous layer was extracted with DCM inthree portions. The combined organic phase was dried over anhydroussodium sulfate and concentrated to provide 41B (161 mg, 94%).

Preparative Example 42

A solution of 41B (200 mg, 0.78 mmol) in THF (10 mL) was treated withdiphenyl cyanocarbonimidate (280 mg, 1.18 mmol) and then heated to 85°C. for 1 h. The mixture was diluted with DCM and sat. sodiumbicarbonate. The biphasic solution was separated and the aqueous layerwas extracted with DCM in three portions. The combined organic phase wasdried over anhydrous sodium sulfate and concentrated to provide (±)-42A(228 mg, 95%). LCMS m/z 305/307 (MH+).

In a manner to that described in Example 1 (Step 7), 42A was coupledwith pyrimidine-5-boronic acid to provide the title compound (±)-42.LCMS m/z 305 (MH+).

Preparative Example 43

A solution of 41B (200 mg, 0.78 mmol) in THF (10 mL) was treated withBrCN (5M/MeCN, 204 uL) and then stirred at RT for 1 h. The mixture wasdiluted with DCM and sat. sodium bicarbonate. The biphasic solution wasseparated and the aqueous layer was extracted with DCM in threeportions. The combined organic phase was dried over anhydrous sodiumsulfate and concentrated to provide (±)-43A (224 mg, 100%). LCMS m/z280/282 (MH+).

In a manner to that described in Example 1 (Step 7), 43A was coupledwith pyrimidine-5-boronic acid to provide the title compound (±)-43.LCMS m/z 280 (MH+).

Preparative Example 44

In a manner similar to that described in Example 41, compound 41B wasreacted with acetamidine hydrochloride (EtOH, RT, 2 h) to provide(±)-44A. LCMS m/z 279/281 (MH+).

In a manner to that described in Example 1 (Step 7), 44A was coupledwith pyrimidine-5-boronic acid to provide the title compound (±)-44.LCMS m/z 279 (MH+).

Preparative Example 45

In a manner similar to that described in Example 41 (Step 5), compound21A was sequentially reacted with methylamine (2M/MeOH, 105° C.overnight in a sealed tube), BH₃—SMe₂, and formamidine acetate toprovide (±)-45C. LCMS m/z 279/281 (MH+).

In a manner to that described in Example 1 (Step 7), 45C was coupledwith pyrimidine-5-boronic acid to provide the title compound (±)-45.LCMS m/z 279 (MH+).

Likewise, reaction of 21A with ethylamine followed by reduction withBH₃—SMe₂, provided 45E, which was cyclized with formamidine acetate toprovide (±)-45F and acetamidine hydrochloride to provide (±)-45G (LCMSm/z 307/309, MH+), respectively. Coupling of (±)-45F withpyrimidine-5-boronic acid provides (±)-45H. Coupling of (±)-45G withpyrimidine-5-boronic acid provides (±)-451.

Preparative Example 46

A solution of 411 (100 mg, 0.37 mmol) in THF (5 mL) was treated withdimethyl dicarbonate (119 uL, 1.12 mmol) followed by TEA (207 uL, 1.49mmol) and stirred at RT for 2 h. The mixture was diluted with DCM andsat. sodium bicarbonate. The biphasic solution was separated and theaqueous layer was extracted with DCM in three portions. The combinedorganic phase was dried over anhydrous sodium sulfate and concentratedto provide 46A (135 mg).

In a manner similar to that described in Example 41, compound 46A wassequentially reacted with BH₃—SMe₂ and formamidine acetate to provide(±)-46C. LCMS m/z 279/281 (MH+).

In a manner to that described in Example 1 (Step 7), 46C was coupledwith pyrimidine-5-boronic acid to provide the title compound (±)-46.LCMS m/z 279 (MH+).

Preparative Example 47

A solution of 45B (21 mg, 0.079 mmol) in DCM (3 mL) was treated with TEA(33 uL, 0.24 mmol) followed by triphosgene (7.8 mg, 0.026 mmol) andstirred at RT for 2 h. The mixture was diluted with DCM and sat. sodiumbicarbonate. The biphasic solution was separated and the aqueous layerwas extracted with DCM in three portions. The combined organic phase wasdried over anhydrous sodium sulfate and concentrated. The crude mixturewas purified (C18 reverse phase HPLC: 5 to 75% water/acetonitrile with0.1% formic acid, over 10 min) to provide (±)-47A (11 mg, 47%). LCMS m/z295/297 (MH+).

In a manner to that described in Example 1 (Step 7), 47A is coupled withpyrimidine-5-boronic acid to provide the title compound (±)-47.

Preparative Example 48

In a manner similar to that described in Example 41 (Step 3), 41B wasreacted with benzamidine HCl (EtOH, 2 h, RT) to provide (±)-48A. LCMSm/z 342 (MH+).

In a manner to that described in Example 1 (Step 7), 48A is coupled withpyrimidine-5-boronic acid to provide the title compound (±)-48.

Preparative Example 49

In a manner similar to that described in Example 43, compound 46B wasreacted with BrCN (1.3 eq, THF, 1 h) to provide (±)-49A. LCMS m/z294/296 (MH+).

In a manner to that described in Example 1 (Step 7), 49A is coupled withpyrimidine-5-boronic acid to provide the title compound (±)-49.

Preparative Example 50

In a manner similar to that previously described (Examples 1, 3 and 5),4-bromo-1-indanone was converted to 4-bromo-2-indanone (50B) and thenfurther to (±)-50F (LCMS m/z 267/269, MH+) and the title compound (±)-50(LCMS m/z 267, MH+)

An alternative conversion of 50A to 50B is described below:

To a solution of compound 50A (0.047 mol, prepared from 10 g4-bromo-1-indanone) in EtOAc/water (220 mL/220 mL) was added NaHCO₃(19.74 g, 0.235 mol) and acetone (34.5 mL, 0.47 mol) at RT. To the abovemixture was added dropwise over 1 hr a solution of Oxone (57.8 g, 0.094mol) in water (220 mL). The reaction mixture was stirred vigorouslyovernight before the layers were separated. The organic phase was washedwith brine (20 mL), dried (Na₂SO₄), filtered, and concentrated underreduced pressure to give crude compound 50G.

To a solution of the crude 50G in THF/CH₂Cl₂ (65 mL/130 mL) was addedIrCl₃ hydrate (158 mg, 0.47 mmol) at RT. The suspension was stirred for2 hrs and filtered through a pad of Celite. The filtrate wasconcentrated under reduced pressure and purified by columnchromatography (15% EtOAc/hexanes) to give compound 50B as an off-whitesolid (6.65 g, 67% over four steps from 4-bromo-1-indanone).

Another alternative conversion of 50A to 50B is described below:

To an ice-cooled mixture of the 50A (crude, 22 g, 0.113 mol) in DCM (360mL) was added sodium bicarbonate (28.5 g, 0.339 mol) followed by mCPBA(35.4 g, 0.16 mol) portionwise. The reaction was slowly warmed to RT andvigorously stirred for 4 h. The mixture was quenched/washed with 10%solution of aq sodium sulfite followed by a final wash with brine. Theorganic phase was dried over anhydrous sodium sulfate and concentratedto dryness to provide 50G (100%).

In a dry round-bottom flask under an atmosphere of nitrogen the crudeepoxide

50G (0.113 mol) was dissolved in benzene (360 mL). The flask was cooledto 0° C. in an ice/water bath and anhydrous zinc diiodide (43.4 g, 0.136mol) was gradually added. The resulting mixture was stirred at 0° C. for10 min before it was warmed to RT and stirred for 4 h. The mixturewashed with water in two portions followed by a final wash with brine.The organic phase was dried over anhydrous sodium sulfate andconcentrated to dryness to provide 50B (99%).

Another alternative preparation of 50E is described below:

A mixture of 3-bromo-o-xylene (20 g, 0.108 mol) in CCl₄ (200 mL) wastreated with NBS (38.5 g, 2.0 eq) and benzoyl peroxide (263 mg, 0.01 eq)and refluxed overnight. The reaction was then cooled to 0° C. andfiltered. The filtrate was concentrated and purified (silica gel,hexanes) to give 50H as a light red oil.

In a manner similar to those described in the literature (Tetrahedon,1999, 55, 14281 and Tetrahedron Letters, 1992, 33, 1565), a mixture ofN-(diphenylmethylene)-glycine ethyl ester (267 mg, 1 mmol) in THF at−78° C. was treated with NaHMDS (1.0N/THF, 1.1 mL, 1.1 eq) and stirred30 min. A solution of compound 50H (343 mg) in THF was added and thereaction was stirred 1 h at −78° C. and then 2 h at RT. The mixture wasagain cooled to −78° C. and treated with NaHMDS (1.0N/THF, 1.1 mL, 1.1eq). The reaction was slowly warmed to RT, stirred overnight, quenchedwith sat. aq. NH₄Cl and extracted with DCM. The organic phase was driedover anhydrous sodium sulfate and concentrated. The residue was taken upin ethyl ether, treated with 1N HCl, and stirred vigorously for 2 h. Thebenzophenone byproduct was removed from reaction mixture by extractingwith diethyl ether. The product was isolated by cooling the aqueouslayer in an ice bath, neutralizing with 1N NaOH, and extracting withdiethyl ether. The ether extract was concentrated to provide 50I.

In a manner similar to that previously described (Example 1), compound50I is reduced with NaBH₄ to provide 50E.

The following compounds were prepared from (±)-50F by Suzuki couplingwith the appropriate boronic ester (1.5 eq) in a fashion similar to thatpreviously described (0.25 eq Pd(dppf)Cl₂, 3 eq Na₂CO₃, 4:1 DME-water,microwave 15 min at 125° C.):

Cpd Structure LCMS (MH+) (±)-50J

269 (±)-50K

255 (±)-50L

283 (±)-50M

284

Preparative Example 51

In a manner similar to that described in Example 2, compound (±)-50 wastreated with 1.5 eq. Boc₂O (1.5 eq NaHCO, THF-water) to provide (±)-51A.The racemic mixture (±)-51A was purified by chiral HPLC (OD column, 25%IPA-hexanes) to provide impure 51B and pure 51C. Compound 51B waspurified further on an AD column (25% IPA-hexanes) to provide purematerial. Compounds 51B and 51C were each deprotected (5:1 DCM:TFA, 3 h)to provide 51D (LCMS m/z 267, MH+) and 51E (LCMS m/z 267, MH+),respectively.

Preparative Example 52

Steps 1-2

In a manner similar to that described in Example 1 (Step 4), compound21A was reducted with NaBH₄ to provide 52A.

A mixture of 52A (200 mg, 0.78 mmol) and n-butyl formate (2 mL) wereheated in a sealed tube for 2d at 130° C. and then cooled to RT. Silicacolumn purification provided the products 52B and 52C.

Steps 3-5

A mixture of 52B (0.78 mmol) in THF (5 mL) was treated with BH₃—SMe₂(2.0 N/THF, 0.78 mL) and then heated at reflux overnight. The reactionwas cooled to RT, treated with EtOH (10 mL) and K₂CO₃ (2 eq), and thenheated at 80° C. for 2 h. The mixture was again cooled and filtered. Thefiltrate was concentrated and purified by column chromatography toprovide 52D (130 mg).

A solution of 52D (130 mg) in EtOH (5 mL) was treated with Br CN (5.0N/MeCN, 0.12 mL) and stirred at RT for 4 h. The mixture was concentratedand purified by column chromatography (7N NH₃-MeOH in DCM) to provide(±)-52E (72 mg, 51%). LCMS m/z 295/297 (MH+).

In a manner similar to that previously described, Suzuki coupling of(±)-52E with 1.5 eq pyrimidine-5-boronic acid (0.2 eq Pd(dppf)Cl₂, 3 eqNa₂CO₃, 4:1 DME-water, microwave 15 min at 120° C.) provided (±)-52.LCMS m/z 295 (MH+).

The enantiomers of (±)-52 were separated (OD semi-prep column, 35%IPA-hexanes, 10 mL/min) to provide 52F (LCMS m/z 295, MH+) and 52G (LCMSm/z 295, MH+).

Preparative Example 53

Steps 1-2

A mixture of 50E (1.0 g, 3.9 mmol) in THF-water (1:1, 40 mL) was treatedwith Boc₂O (1.28 g, 1.5 eq) and Na₂CO₃ (491 mg, 1.5 eq), stirred at RT,and then extracted with EtOAc. The organic layers were combined andconcentrated to give the protected product (1.25 g, 90%) as a creamcolored solid.

A mixture of the Boc protected alcohol (660 mg, 1.85 mmol) in DCM (20mL) was treated with TPAP (65 mg, 0.1 eq) and NMO (282 mg, 1.3 eq) andstirred at RT for 3 h. The reaction was then diluted with hexane (20mL), stirred 10 min, and filtered. The filtrate was concentrated andpurified by silica gel chromatography to provide 53A (490 mg).

Steps 3-4

A solution of 53A (430 mg, 1.21 mmol) in THF (15 mL) was cooled to −78°C. and treated with MeMgBr (3.0 N/THF, 0.93 mL, 2.3 eq) dropwise. Themixture was allowed to warm to RT slowly and then was quenched with sat.aq. NH₄Cl at 0° C. The reaction was extracted with DCM. The combinedorganic extracts were dried over Na₂SO₄, concentrated and purified toprovide a mixture of 53B (minor product) and 53C (major product).

Compound 53C was converted to 53B by the following procedure: A mixtureof 53C (145 mg, 0.5 mmol) and Ba(OH)₂ in dioxane-water (1:1, 30 mL) washeated at 100° C. until LCMS analysis indicated consumption of the SM.The mixture was cooled and diluted with EtOAc and water. The organiclayer was separated, dried over over Na₂SO₄, concentrated and purifiedto provide a mixture of 53B (110 mg, 81%).

Alternatively, compound 53A was converted directly to compound 53B byuse of DCM as solvent: A mixture of 53A (3.49 g, 9.8 mmol) in DCM (50mL) was cooled to −78° C. and treated with MeMgBr (3.0 N/THF, 8.2 mL,2.5 eq) dropwise. The mixture was allowed to warm to RT, stirred 1 h,and then was quenched with sat. aq. NH₄Cl at 0° C. The reaction wasextracted with DCM. The organic layer was dried over Na₂SO₄,concentrated and purified to provide 53B (3.61 g) as a white foam.

Steps 5-6

A mixture of the amino alcohol 53B (100 mg, 0.37 mmol) and BrCN (5.0N/MeCN, 0.09 mL) in EtOH (7 mL) was stirred at RT for 4 h. The mixturewas concentrated and purified by column chromatography (7N NH₃-MeOH inDCM) to provide (±)-53D.

Compound (±)-53D was subjected to Suzuki coupling withpyrimidine-5-boronic acid (cat. Pd(dppf)Cl₂, Na₂CO₃, 4:1 DME-water,microwave 15 min at 120° C.) to provide (±)-53. LCMS m/z 295 (MH+).

The two sets of diastereomers were separated by silica gelchromatography. The less polar set was further purified by chiral HPLC(AD column, 15% IPA-hexanes with 0.1% DEA) to provide 53E (LCMS m/z 295,MH+) and 53F (LCMS m/z 295, MH+). The more polar set was furtherpurified by chiral HPLC(OD column, 10% EtOH-hexanes with 0.1% DEA) toprovide 53G (LCMS m/z 295, MH+) and 53H (LCMS m/z 295, MH+).

Alternatively, enantiomerically pure amino ester 21B was brought throughthe sequence outlined above to provide a mixture of 53F and 53H, whichwere separated by chiral HPLC(OD column, 10% EtOH-hexanes with 0.1% DEAand then AD column, 15% IPA-hexanes with 0.1% DEA).

Preparative Example 54

In a manner similar to that described in Example 53, compound 50E wassequentially protected with Boc₂O, oxidized with TPAP/NMO or Dess-Martinreagent, and treated with MeMgBr (in DCM, −78° C. to RT overnight or inTHF, 1 h, −78° C.) to provide 54C. In a manner similar to thatpreviously described, 54C was deprotected with TFA, cyclized withEtOC(O)NCS/Hg(OAc)₂, and hydrolyzed with LiOH to provide (±)-54E. Suzukicoupling with pyrimidine-5-boronic acid provided (±)-54 (LCMS m/z 281,MH+) as a mixture of four stereoisomers.

The four stereoisomers of (±)-54 were separated by chiral HPLC (LuxCellulose-2 column using 15% IPA-hexanes with 0.1% DEA followed by ADcolumn using 15% IPA-hexanes with 0.1% DEA) to provide 54G (LCMS m/z281, MH+), 54H (LCMS m/z 281, MH+), 541 (LCMS m/z 281, MH+), and 54J(LCMS m/z 281, MH+).

Alternatively, the enantiomers of compound 50D and 54A were separated bySFC (OD column with 10% MeOH and AD with 20% MeOH, respectively). Thediastereomers of alcohols (54K and 54L) were separated by silicachromatography (2-25% EtOAc/hexanes).

Preparative Example 55

Compound 55A (prepared from 54L as described in Example 54) wasdeprotected, cyclized, and hydrolyzed as described above to provide 55B.In a manner similar to that described in previous examples, 55B iscoupled with the appropriate boronic ester, boronic acid, or tincompound to provide the following compounds.

Preparative Example 56

To the mixture of 531 (93 mg, 0.360 mmol, derived by reduction of 21Bwith NaBH₄) and DIPEA (78 μL, 0.432 mmol) in DMF (3 mL) was addedtrimethylorthoacetate (55 μL, 0.432 mmol). The mixture was kept stirringat 115° C. for 16 h. The mixture was diluted H₂O (5 mL) and thenextracted with EtOAc (2×10 mL). The combined organic layer was washedwith brine (10 mL), dried over anhydrous MgSO₄, and concentrated. Theresidue was purified (silica gel, 1:1 EtOAc-Hexane) to obtain (±)-56A asa white solid (50 mg). LCMS m/z 280/282, (MH+).

A mixture of compound (±)-56A (50 g, 0.178 mol), pyrimidine-5-boronicacid (36 mg, 0.268 mmol), Pd(PPh₃)₂Cl₂ (19 mg, 0.15 mol %) and Na₂CO₃(57 mg, 0.534 mmol) in DME-H₂O (2 mL-0.5 mL) was microwaved (120° C., 30min) and then extracted with CH₂Cl₂ (2×10 mL). The organic layer waswashed with brine (6 mL), dried over anhydrous MgSO₄, and concentrated.The residue was purified by PTLC (1: 12 mixture of 2N NH₃-MeOH in DCM)to obtain (±)-56 as a white foam (20 mg). LCMS m/z 280 (MH+).

Preparative Example 57

Step 1

2.5M n-BuLi in hexane (260 μL, 0.650 mmol) was added to a suspension ofmethyltriphenylphosphonium bromide (211 mg, 0.600 mmol) in THF (3 mL).The mixture turned into an orange suspension. After stirring at RT for30 min, the solution of aldehyde 53A (200 mg, 0.565 mmol) in THF (1 mL)was added dropwise. The resultant mixture was kept stirring at RT for 1h and a white precipitate formed. The mixture was diluted with sat. aq.NH₄Cl (3 mL) and extracted with EtOAc (2×10 mL). The combined organicwas washed with brine (10 mL), dried over anhydrous MgSO₄, andconcentrated. The residue was purified (silica gel, 1:10 EtOAc-Hexane)to obtain 57A as a white solid (120 mg). LCMS m/z 352/354 (MH+).

Step 2

A solution of 57A in THF (1 mL) solution at 0° C. was treated withBH₃-THF (1M, 1.56 mL, 1.56 mmol) and stirred at 0° C. for 1 h. Thereaction was treated with 1N NaOH (1.5 mL), immediately followed by H₂O₂(30%). The ice bath was removed, and the reaction mixture was keptstirring at RT for 1 h. The reaction was extracted with EtOAc (2×10 mL).The combined organic was washed with H₂O (10 mL), dried over anhydrousMgSO₄, and concentrated. The residue was purified (silica gel, 1:2EtOAc-Hexane) to obtain 57B as a white solid (31 mg). LCMS m/z 370/372(MH+).

Step 3:

TFA (1 mL) was added to the solution of compound 57B (120 mg, 0.324mmol) in CH₂Cl₂ (2 mL). The reaction was kept stirring at RT for 2 h.The mixture was diluted with CH₂Cl₂ (10 mL) and basified with 50% NH₄OH(v/v, 6 mL). The aqueous layer was extracted once more with CH₂Cl₂ (10mL). The combined organic was dried over anhydrous MgSO₄, andconcentrated to obtain compound 57C as a white solid (67 mg). LCMS m/z270/272 (MH+).

Step 4

A solution of 57C (67 mg, 0.248 mmol) in EtOH (1 mL) at 0° C. wastreated with BrCN (5M/CH₃CN, 60 μL, 0.3 mmol) and then stirred at RT for16 h. The mixture was concentrated, diluted with CH₂Cl₂ (10 mL), andbasified with sat. aq. NaHCO₃ (5 mL). The aqueous layer was extractedonce more with CH₂Cl₂ (10 mL). The combined organic layers were driedover anhydrous MgSO₄, and concentrated. The residue was purified (PTLCeluting with DCM-MeOH (2N NH₃)=10:1) to obtain (±)-57D as a white foam(15 mg). LCMS m/z 295/297 (MH+).Step 5

Compound (±)-57D (15 mg, 0.05 mmol), pyrimidine-5-boronic acid (7.6 mg,0.06 mmol), Pd(PPh₃)₂Cl₂ (5.2 mg, 0.15 mol %) and Na₂CO₃ (21 mg, 0.2mmol) were mixed in DME-H₂O (1 mL-0.25 mL) and microwaved at 120° C. for45 min. The mixture was extracted with CH₂Cl₂ (2×10 mL). The organic waswashed with brine (6 mL), dried over anhydrous MgSO₄, and concentrated.The residue was purified (PTLC eluting with DCM-MeOH (2N NH₃)=10:1) toobtain the title compound (±)-57 as a white film (1.2 mg, LCMS m/z 295,MH+), and (±)-57E as a white film (1.4 mg, LCMS m/z 270, MH+).

Preparative Example 58

Step 1

3-bromo-phenylacetic acid (6.5 g, 30 mmol) was treated with oxallylchloride (10 mL) at RT for 2 h, and then refluxed at 80° C. for 4 hr.The mixture was cooled to RT and concentrated to give crude acetylchloride without further purification.

A mixture of AlCl₃ (12 g, 90 mmol) in DCM (90 mL) at −20° C. was addedto the crude acetyl chloride in DCM (10 mL) and stirred for 0.5 h at−20° C. Allyl trimethylsilane (5.14 g, 54 mmol) was added dropwise. Themixture was further stirred at −20° C. for 2 h and then refluxed for 1.5h before cooling to RT. An aq. HCl solution (2N, 30 mL) was slowly addedto the reaction at 0° C., then extracted with Et₂O thoroughly. Thecombined organic layers were dried over Na₂SO₄, concentrated andchromatographed (0% to 10% EtOAc/Hexane) to give the desired product 58Aand 58B as a mixture (1/1.5, 3 g, 42%).

Steps 2-7

A mixture of 58A and 58B (1/1.5, 3.0 g, 12.5 mmol, 58B not shown),(NH₄)₂CO₃ (5 g, 50 mmol), and KCN (1.63 g, 25 mmol) in 1:1 EtOH—H₂O (20mL) was heated in a sealed tube overnight at 85° C. The reaction wasthen cooled to RT, diluted with water (˜400 mL) and stirred for 2 h. Theprecipitate was filtered and dried in vacuo overnight to provide amixture of 5- and 7-Br hydantoins as exemplified by 58C (3.5 g, 90%,5-sub/7-sub=1/1.5, 7-bromo not shown).

A mixture of 5- and 7-Br hydantoins (as exemplified by 58C, 3.5 g, 11.3mmol) and LiOH—H₂O (3.18 g, 75.6 mmol) in H₂O (100 mL) was refluxedovernight. The reaction was then cooled to 0° C., acidified with 12 NHCl, and concentrated to give a mixture of 5- and 7-Br amino acids as asolid.

Thionyl chloride (9 mL) was carefully added to MeOH (300 mL) at 0° C.The resulting mixture was then added to a flask charged with the aminoacid product. The reaction was heated to reflux overnight and thencooled and concentrated. The residue was taken up in sat. aq. NaHCO₃ andextracted EtOAc (2×). The combined organic layers were dried over Na₂SO₄and concentrated. Chromatography (0-50% EtOAc/hex) provided a mixture of5- and 7-Br aminoesters (as exemplified by 58D) as a red oil.

The mixture of aminoesters (270 mg, 0.98 mmol) was dissolved inanhydrous MeOH (2 mL) and then treated with NaBH₄ (60 mg, 1.5 mmol). Thereaction was concentrated after TLC indicated consumption of SM (1 h).DCM (20 mL) was added to the residue and washed with brine (10 mL). Theorganic layers were dried over Na₂SO₄, concentrated and chromatographed(0% to 20% MeOH/DCM) to give the desired aminoalcohols (as exemplifiedby 58E, LCMS m/z 270/272, MH+).

A mixture of aminoalcohols (120 mg, 0.45 mmol), pyrimidine-5-boronicacid (62 mg, 0.5 mmol), Pd(PPh₃)₄ (63 mg, 0.09 mmol), Na₂CO₃ (144 mg,1.35 mmol) in 4:1 DME-H₂O (5 mL) were heated at 120° C. in a microwavefor 1 h. The reaction concentrated, diluted with water and extractedwith DCM (4×). The layers were separated. The combined organic layerswere dried over Na₂SO₄, concentrated and chromatographed (2-5% ofNH₃-MeOH/DCM) to give the desired product (100 mg, 83%, mixture of 5-and 7-substitutions as exemplified by 58F, LCMS m/z 270, MH+).

A solution of 58F (82 mg, 0.31 mmol) in EtOH/DCM (1:1, 2 mL) was treatedwith BrCN (0.1 mL, 5.0 M in CH₃CN) and was stirred at RT overnight. Themixture was diluted with water and extracted with DCM (4×). The layerswere separated. The combined organic layers were dried over Na₂SO₄,concentrated and chromatographed (2-5% of NH₃-MeOH/DCM) to give (±)-58(40 mg, 44%). LCMS m/z 295 (MH+)

Compounds 58G (LCMS m/z 295, MH+) and 58H (LCMS m/z 295, MH+) were alsoisolated during this procedure:

Preparative Example 59

A solution of compound 38E in DCM is treated with Deoxy-Fluor(F₃S—N(CH₂CH₂OMe)₂) and refluxed until the starting material isconsumed. The reaction is cooled to RT, poured onto sat. aq. NaHCO₃ andextracted with DCM (2×). The organic layers are dried over Na₂SO₄,concentrated and chromatographed on silica gel to provide the product59. Alternatively, DAST (F₃S-NEt₂) is used as the fluorinating reagent.

The following compounds are synthesized in a similar manner from theindicated starting materials:

Cpd Structure SM 59A

38F 59B

diastereomer 1

38G (diastereomer 1) 59C

diastereomer 2

38H (diastereomer 2) 59D

diastereomer 1

38I (diastereomer 1) 59E

diastereomer 2

38J (diastereomer 2)

Preparative Example 60

In a manner similar to that described in Examples 57 and 59, compound(±)-23 is subjected to hydroboration/oxidation and fluorination toprovide (±)-60.

Preparative Example 61

Ozone is bubbled through a mixture of compound (±)-23 in DCM at −78° C.for 30 min. Air is then bubbled in for 10 min. The reaction is thentreated with dimethylsulfide (10 eq), allowed to warm to RT,concentrated and purified by flash chromatography. In a manner similarto that previously described, the resulting aldehyde (±)-61A was reducedand fluorinated to provide (±)-61.

Preparative Example 62

In a manner similar to that described in Example 53, vinylmagnesiumbromide is added to compound 54B. In a manner similar to that previouslydescribed, the resulting product 62A is deprotected, cyclized, andhydrolyzed to give (±)-62B. Following the sequence described previously,(±)-62B is advanced to (±)-62D and then coupled with pyrdimine-5-boronicacid to provide the title compound (±)-62.

Preparative Example 63

In a manner similar to that described in Example 53, compound 54B istreated with CD₃MgBr (prepared from CD₃Br, see J. Am. Chem. Soc. 1989,111, 3897) and then advanced to (±)-63.

Preparative Example 64

A solution of 50D in THF is treated with LiAlD₄ at RT for 1 h to provide64A, which is further progressed to (±)-64 in a manner similar to thatoutlined in Example 54.

Preparative Example 65

Step 1

A suspension of 3-bromo-o-xylene (80 g, 432 mmol), NBS (154 g, 864 mmol)and AIBN (2,2′-azobis(2-methylpropionitrile, 2.0 g, 12.3 mmol) inanhydrous CCl₄ (400 mL) was gradually warmed to boiling and thenrefluxed for 2 h. The mixture was cooled to RT and filtered. Thefiltrate was concentrated and filtered through a silica pad, elutingwith 10% EtOAc-hexanes. The resulting product was concentrated, cooledin the freezer and then triturated with cold hexanes to obtain 65A (110g). Additional product could be obtained from the mother liquor.

Steps 2-3

A solution of NaHMDS (1.0M/THF, 200 mL, 1.05 eq) in THF was cooled to−78° C. and treated dropwise with a solution ofN-(diphenylmethylene)glycine ethyl ester (50.68 g, 1.0 eq) in THF. Thereaction was stirred 30 min at −78° C. and then treated with tribromide65A (65 g, 1.0 eq) in THF dropwise. The reaction was allowed to slowlywarm to RT overnight. The mixture was then cooled to −78° C. and treateddropwise with NaHMDS (1.0M/THF, 209 mL, 1.1 eq). The reaction was againallowed to slowly warm to RT overnight. The mixture was quenched withice and extracted with Et₂O.

The organic layer was treated with HCl (2N, 1 L) and stirred vigorouslyuntil analysis indicated complete conversion of the intermediate imineto 65B. The layers were then separated, discarding the organic layer.The aqueous layer was cooled in an ice-bath and neutralized with 5% NaOH(or aq. NH4OH) and extracted with DCM. The DCM layer was dried overNa₂SO₄, concentrated and chromatographed (5-50% EtOAc/hex) to give 65B.

Steps 4-5

Compound 65B was treated with Boc₂O as previously described. Theresulting protected amino ester (0.14 g, 0.364 mmol) was taken up inanhydrous pentane (3 mL) and treated with TMS-methyllithium (1.0M/pentane, 1.1 mL, 3.0 eq) at 0° C. The reaction was stirred 2.5 h at 0°C., quenched with MeOH (1 mL), and stirred at RT for 1 h. The mixturewas diluted with water and extracted with ether (3×50 mL). The etherlayer was dried over Na₂SO₄, concentrated and chromatographed to give65C.

Compound 65C is reduced with NaBH₄ to give alcohol 54C. Alternatively,65C is reduced in a stereoselective manner with(S)-2-methyl-CBS-oxazaborolidine/borane or(R)-2-methyl-CBS-oxazaborolidine/borane as described in Example 66.

Preparative Example 66

A solution of compound 66A (995 mg, 2.79 mmol, prepared from 54L asdescribed in Example 54) in DCM (25 mL) was treated with the Dess-Martinperiodinane reagent (1.78 g, 4.19 mmol) and stirred for 3 h at RT. Thereaction was then quenched with a solution of Na₂S₂O₃ in water andstirred at RT. The organic layer was separated, washed with aqueousNa₂S₂O₃. The aqueous layer was further extracted with EtOAc. Thecombined organic layers were sequentially washed with sat. aq. NaHCO₃(2×), brine and water. The organic layer was then dried over Na₂SO₄,concentrated and chromatographed (5-20% EtOAc/hex) to give 66B as alight yellow foam. LCMS m/z 352/354 (MH+)

A mixture of BH₃-DMS (2.54 mL of 2.0N solution/THF) and(S)-2-methyl-CBS-oxazaborolidine (5.08 mL of 2.0N solution/THF) in THF(30 min) was stirred for 10 min at RT. The reaction was cooled to 0° C.and then slowly treated with a solution of compound 65C (1.63 g, 4.62mmol) in THF (30 mL) via addition funnel. The reaction was allowed towarm to RT slowly, stirred overnight, quenched with water, and stirredan additional 2 h. The mixture was then extracted with EtOAc, dried overNa₂SO₄, concentrated and chromatographed (5-20% EtOAc/hex) to give 55Aas a white solid (1.45 g). LCMS m/z 356/358 (MH+).

Preparative Example 67

Step 1

A mixture of 3-bromo-6-fluoro-o-xylene (25.37 g, 432 mmol) in anhydrousCCl₄ (250 mL) was treated with NBS (44.5 g, 864 mmol) and benzoylperoxide (310 mg) and then heated at reflux overnight. The mixture wascooled to 0° C. and filtered, washing with hexanes. The filtrate wasconcentrated and chromatographed (hexanes) to give 67A as an colorlessoil (41.57 g, with minor mono-bromo impurities).

Steps 2-4

In a manner similar to that described previously (Example 65, Steps 2-3and Example 1, Step 4), compound 67A was sequentially treated withN-(diphenylmethylene)glycine ethyl ester, HCl, and NaBH₄ to provide 67C.

Steps 5-6

A mixture of amino alcohol 67C (671 mg, 2.6 mmol) in anhydrousacetonitrile (14 mL) was treated with BrCN (3M/DCM, 1.06 mL, 1.24 eq)and iPr₂NEt (0.53 mL, 1.19 eq). The reaction was stirred at RT for 18 hand then quenched with aq. NH₃ and extracted with DCM. The organicextracts were concentrated to give 67D (730 mg) as a white crystallinesolid.

In a manner similar to that previously described, 67D was coupled withpyrimidine-5-boronic acid to provide (±)-67. MS m/z 285 (MH+).

The following compounds were prepared following procedures similar tothose exemplified in the examples above.

LCMS Cpd Structure (MH+) (±)-100

283 (±)-101

297 (±)-102

297 (±)-103

280 (±)-104

341 (±)-105

294 (±)-106

330 (±)-107

330 (±)-108

282 109

310 110

310 111

296 (±)-112

310 (±)-113

298 (±)-114

297 115

415 116

415 117

281 118

281 119

286 120

286 121

279 122

324 123

310 124

305 125

311 126

311 (±)-127

286 (±)-128

281 (±)-129

286 (±)-130

311 (±)-131

286 (±)-132

311 (±)-133

311 (±)-134

324 135

295/297 136

295/297 137

295/297 138

295 139

295 140

295 141

281 142

281 143

279 144

279 145

280 146

280 147

298 148

281 149

281 150

294 151

294 152

309 153

309 (±)-154

283 (±)-155

265/267 (±)-156

263 (±)-157

267 (±)-158

253 (±)-159

269 (±)-160

265/267 (±)-161

263 (±)-162

265 (±)-163

267 (±)-164

253 (±)-165

269 (±)-166

269 (±)-167

269 (±)-168

305 (±)-169

305/307 (±)-170

304 (±)-171

305/307 (±)-172

305 (±)-173

304 (±)-174

280/282 (±)-175

280 (±)-176

278 (±)-177

282 (±)-178

296 (±)-179

297 (±)-180

268 (±)-181

284 (±)-182

284 (±)-183

279 (±)-184

298 (±)-185

293 (±)-186

280/282 (±)-187

278 (±)-188

280 (±)-189

282 (±)-190

296 (±)-191

297 (±)-192

268 (±)-193

284 (±)-194

278 (±)-195

282 (±)-196

296 (±)-197

297 (±)-198

268 (±)-199

284 (±)-200

284 (±)-201

293/295 (±)-202

293 (±)-203

294/296 (±)-204

293/295 (±)-205

294 (±)-206

293 (±)-207

298 (±)-208

297 (±)-209

281/283 (±)-210

281 (±)-211

285 212

279 213

279 214

279 215

279 216

283 217

283 218

283 219

283 220

267 221

267 222

267 223

267 224

279/281 225

279/281 227

265 228

265 229

280 230

280 231

269 232

269 233

284 234

284 235

253 236

253 237

268 238

268 239

293 240

293 241

294 242

294 243

297 244

297 245

298 246

298 247

281 248

281 249

282 250

282 251

278 252

279 253

279 254

268 255

282 256

313 257

284 258

280 259

318 260

355 261

298 262

293 (±)-263

280/282 (±)-264

280 (±)-265

278 (±)-266

279 (±)-267

293 (±)-268

310 (±)-269

296 (±)-270

310 (±)-271

265/267 (±)-272

265 (±)-273

305/307 (±)-274

305 (±)-275

280/282 (±)-276

280 (±)-277

295 (±)-278

295 (±)-279

295 (±)-280

295 (±)-281

445 (±)-282

341 (±)-283

280 (±)-284

279 (±)-285

309 (±)-286

295 (±)-287

284 288

281 (±)-289

308 (±)-290

294 (±)-291

295 (±)-292

312 (±)-293

319 (±)-294

334 (±)-295

294 (±)-296

293 (±)-297

300 298

300 299

300 (±)-300

294 301

294 302

294 (±)-303

325 304

325 305

325 (±)-306

300 307

300 308

300 (±)-309

294 (±)-310

325 311

325 312

325 313

294 314

294 315

294 316

294 317

325 318

325 319

337 320

337 321

363 322

363 323

300 324

294 (±)-325

281Assay:

Efficacy agonist activity values (Emax, GTPγS assay) for α2A and α2Cwere determined by following the general procedure detailed by Umlandet. al (“Receptor reserve analysis of the human α_(2c)-adrenoceptorusing [³⁵S]GTPγS and cAMP functional assays” European Journal ofPharmacology 2001, 411, 211-221). For the purposes of the presentinvention, a compound is defined to be a specific or at leastfunctionally selective agonist of the α2C receptor subtype if thecompound's efficacy at the α2C receptor is ≧30% Emax (GTPγS assay) andits efficacy at the α2A receptor is 35% Emax (GTPγS assay).Additionally, for the purposes of this invention, a compound is definedto be an antagonist of the α2C receptor subtype if the compound'sefficacy at the α2C receptor is <30% Emax (GTPγS assay) and the K_(i) atthe α2C receptor subtype was <500 nM, preferentially <200 nM, and mostpreferentially <20 nM.

The following compounds were evaluated to be active or functionallyselective agonists of the α2C receptor subtype based on the previouslydefined definition:

(±)-1, (±)-1H, 2D, 2E, (±)-4, (±)-5H, (±)-5L, (±)-7A, (±)-7B, (±)-7C,(±)-10, (±)-15A, (±)-15C, (±)-17, (±)-18A, (±)-20, 21H, 21L, 21M, 21N,21O, 22, 22E, 22F, 22G, (±)-23, (±)-23C, (±)-23D, (±)-24, 24F, 24H, 24I,26, 26D, 28G, (±)-29, (±)-29A, (±)-30, 30D, 30F, (±)-34A, (±)-34I,(±)-34J, (±)-34K, (±)-37, (±)-37I, (±)-38, 38E, 38F, 38G, 38H, 38I, 38J,(±)-41, (±)-41D, (±)-41F, (±)-41G, (±)-41H, (±)-43, (±)-44, (±)-45,(±)-46, (±)-50, 51D, 51E, (±)-52, 52F, (±)-53, 53F, 53H, 541, (±)-56,(±)-100, (±)-103, (±)-105, 110, 117, 118, 120, 121, 122, 123, 126,(±)-127, (±)-128, (±)-130, (±)-131, (±)-132, 141, 144, 146, (±)-154,(±)-159, (±)-165, (±)-175, (±)-194, (±)-205, (±)-206, (±)-207, 212, 214,215, 216, 220, 222, 227, 228, 229, 230, 231, 233, 235, 237, 239, 240,241, 242, 245, 249, 251, 252, 253, 254, 257, 259, 260, 261, 262,(±)-276, (±)-284, (±)-287, 288, (±)-290, 307, 309, 312, 313, and 323.

The following compounds were evaluated to be an antagonist of the α2Creceptor subtype based on the previously defined definition (K_(i)<200nM):

(±)-1G, (±)-3, (±)-3D, (±)-6J, (±)-6K, (±)-6L, (±)-8, (±)-8E, (±)-8I,(±)-8R, (±)-8S, (±)-10B, (±)-11, (±)-16, 21I, 21J, 21K, 25F, 25G,(±)-340, (±)-50K, (±)-50L, (±)-50M, (±)-57, (±)-58, (±)-101, (±)-112,(±)-113, (±)-114, 119, (±)-129, (±)-133, 142, 143, 145, 149, 150, 151,213, and 238.

While the present invention has been described with in conjunction withthe specific embodiments set forth above, many alternatives,modifications and other variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall within the spirit and scope of thepresent invention.

What is claimed is:
 1. A compound represented by Formula I

or a pharmaceutically acceptable salt thereof wherein: wherein

is a single bond when R¹⁵ is present or double bond when R¹⁵ is absent;R¹ is a ring selected from the group consisting of cycloalkyl,cycloalkenyl, aryl, heterocyclyl, heterocyclenyl, and heteroaryl, eachof which is optionally substituted with at least one R¹²; R³ isindependently selected from the group consisting of H, —OH, halo, —CN,—NO₂, —S(O)_(p)R⁷, —NR⁷R^(7′), —S(O)_(p)NR⁷R^(7′), and (═O), and alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups optionally substituted with at least one R⁵,provided that when w is 3, no more than 2 of the R³ groups may be (═O);R⁴ is independently selected from the group consisting of H, D, —OH,halo, —CN, —S(O)_(p)R⁷, —NR⁷R^(7′) and —S(O)_(p)NR⁷R^(7′), and alkyl,deuterated alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, and heterocyclylalkyl groups optionally substituted withat least one R⁵; R^(4′) is independently selected from the groupconsisting of H, D, halo, —OH, and alkyl, deuterated alkyl and alkoxy;or R⁴ and R^(4′) may be taken together to form (═O); R⁵ is independentlyselected from the group consisting of H, halo, —OH, —CN, —NO₂,—NR⁷R^(7′), and —S(O)_(p)R⁷, and alkyl, alkoxy, alkenyl, alkenyloxy,alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each ofwhich is optionally substituted with at least one of halo, —OH, —CN,—NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷ substituents and/or 1 or 2 (═O)groups, R⁷ is independently selected from the group consisting of H andalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl,cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted one or more times byR¹²; R^(7′) is independently selected from the group consisting of H andalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloclenyl,cyclocyclenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,hetrocyclenyl, hetrocyclenylalkyl, heteroaryl, and heteroarylalkylgroups, each of which is optionally substituted one or more times byR¹²; or a) when a variable is —NR⁷R^(7′), —C(O)NR⁷R^(7′) or—SO₂NR⁷R^(7′), R⁷ and R^(7′) together with the nitrogen atom to whichthey are attached independently form a 3- to 8-membered heterocyclyl,heterocyclenyl or heteroaryl ring having, in addition to the N atom, 1or 2 additional hetero atoms independently selected from the groupconsisting of O, N, —N(R⁹)— and S, wherein said rings are optionallysubstituted by 1 to 5 independently selected R¹² moieties and/or 1 or 2(═O) groups, or b) when a variable is —(CH₂)_(q)ON═CR⁷R^(7′), R⁷ and R⁷together with the carbon atom to which they are attached independentlyform a 3- to 8-membered cycloalkyl, cycloalkenyl, aryl, heterocyclyl,heterocyclenyl or heteroaryl ring, wherein said heterocyclyl,heterocyclenyl or heteroaryl rings have 1-3 heteroatoms which areindependently selected from the group consisting of O, N, —N(R⁹)— and S,wherein said rings are optionally substituted by 1 to 5 independentlyselected R¹² moieties and/or 1 or 2 (═O) groups, R⁹ is independentlyselected from the group consisting of H, —C(O)—R¹⁹, —C(O)—OR¹⁰, and—S(O)_(p)—R¹⁰ and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl groups, each of which is optionallysubstituted with at least one of halo, —OH, —CN, —NO₂, —N(R¹¹⁾ ₂, and—S(O)_(p)R¹¹ substituents and/or 1 or 2 (═O) groups; and R¹⁰ isindependently selected from the group consisting of H, and alkyl,alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups groups, each of which is optionally substitutedwith at least one of halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹substituents and/or 1 or 2 (═O); R¹¹ is a moiety independently selectedfrom the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy,alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each of which isoptionally substituted by at least one substituent independentlyselected from the group consisting of halo, —OH, —CN, —NO₂, —N(R¹¹)₂,and —S(O)_(p)R^(11′) and/or 1 or 2 (═O) groups; R^(11′) is independentlyselected from the group consisting of H, alkyl, alkoxy, alkenyl,alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R¹² isindependently selected from the group consisting of H, halo, —OH, —CN,—NO₂, —N(R¹¹)₂, C(O)—OR¹⁴, —N(R¹⁴)—C(O)—R¹⁴, —N(R¹⁴)—C(O)₂—R¹⁴,—C(O)—N(R¹¹)₂, —N(R¹⁴)—S(O)₂—R¹¹, —S(O)₂—N(R¹¹)₂ and —S(O)_(p)R¹¹ and/or1 or 2 (═O) groups, and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl,heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl,heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl,heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy,and heterocyclenylalkoxy groups, each of which in turn is optionallysubstituted by at least once by a substituent selected from the groupconsisting of H, alkyl, haloalkyl, halo, —OH, optionally substitutedalkoxy, optionally substituted aryloxy, optionally substitutedcycloalkoxy, optionally substituted heteroaryloxy, optionallysubstituted heterocyclenyloxy, —CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹and/or 1 or 2 (═O) groups, wherein said optionally substituted alkoxy,aryloxy, optionally substituted cycloalkoxy, optionally substitutedheteroaryloxy, and heterocyclenyloxy when substituted are substitutedone or more times by R¹¹; R¹⁴ is independently H, alkyl, or aryl; R¹⁵ isabsent or is independently selected from the group consisting of H,—C(O)—R¹⁰, —C(O)—OR¹⁰, —C(O)—N(R⁷)(R^(7′)), and —S(O)_(p)—R¹⁰,SO₂—NR⁷R^(7′) and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each ofwhich is optionally substituted with at least one of halo, —OH, —CN,—NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷ and/or 1 or 2 (═O) groupssubstituents, and —C(═O)R⁷, —C(═O)OR⁷, —C(═O)NR⁷R^(7′), —SO₂R¹⁰ and—SO₂NR⁷R^(7′); q is independently an integer from 0-10; p isindependently an integer from 0-2; and w is an integer from 0-3.
 2. Thecompound according to claim 1 wherein R¹ is optionally substituted aryl,optionally substituted arylalkyl, optionally substituted arylalkoxy,optionally substituted pyridyl, optionally substituted pyrimidyl,optionally substituted furanyl, optionally substituted thiophenyl,optionally substituted quinolinyl, optionally substituted indolyl,optionally substituted pyrrolyl, and optionally substitutedpyrrolidinyl, optionally substituted pyrazolyl, optionally substitutedoxazolyl, optionally substituted isoxazolyl, optionally substitutedimidazole, optionally substituted pyridazinyl, optionally substitutedpyrazinyl, optionally substituted tetrazolyl, optionally substitutedimidazopyrimidinyl, optionally substituted thiazolyl, optionallysubstituted isothiazolyl, optionally substituted indazolyl, optionallysubstituted benzofuranyl, optionally substituted benzothiophenyl,optionally substituted isoquinolyl, optionally substitutedbenzimidazolyl, optionally substituted benzthiazolyl, optionallysubstituted quinoxalinyl, wherein said groups may be optionallysubstituted 1 to 3 times with substitutents selected from the groupconsisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxyl; R⁴ is independentlyselected from the group consisting of H, halo, —OH, halo, and —CN, andalkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups optionally substituted with at least one R⁵;R^(4′) is independently selected from the group consisting of halo andalkyl; R⁵ is independently selected from the group consisting of H,halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷, and alkyl, alkoxy,alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl groups, each of which is optionally substituted withat least one of halo, —OH, —CN, —NO₂, —NR⁷R^(7′), and —S(O)_(p)R⁷substituents and/or 1 or 2 (═O); R⁷ is independently selected from thegroup consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl,heteroaryl, and heteroarylalkyl groups, each of which is optionallysubstituted one or more times by R¹²; R^(7′) is independently selectedfrom the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloclenyl, cyclocyclenylalkyl, aryl, arylalkyl,heterocyclyl, heterocyclylalkyl, hetrocyclenyl, hetrocyclenylalkyl,heteroaryl, and heteroarylalkyl groups, each of which is optionallysubstituted one or more times by R¹²; R¹¹ is a moiety independentlyselected from the group consisting of H and alkyl, alkoxy, alkenyl,alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, eachof which is optionally substituted by at least one substituentindependently selected from the group consisting of halo, —OH, —CN,—NO₂, —N(R^(11′))₂, and —S(O)_(p)R¹¹ substituents and/or 1 or 2 (═O);R^(11′) is independently selected from the group consisting of H, alkyl,alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, andheterocyclylalkyl; R¹² is independently selected from the groupconsisting of H, halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹,and/or 1 or 2 (═O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, aryloxy, arylalkyl,heteroaryl, heteroaryloxy, heteroarylalkyl, heterocyclyl,heterocyclenyl, heterocyclenyloxy, heterocyclylalkyl,heterocyclenylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy,and heterocyclenylalkoxy groups, each of which in turn is optionallysubstituted by at least one by a substituent selected from the groupconsisting of H, alkyl, haloalkyl, halo, —OH, optionally substitutedalkoxy, optionally substituted aryloxy, optionally substitutedcycloalkoxy, optionally substituted heteroaryloxy, optionallysubstituted heterocyclenyloxy, —CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹and/or 1 or 2 (═O), wherein said optionally substituted alkoxy, aryloxy,optionally substituted cycloalkoxy, optionally substitutedheteroaryloxy, and heterocyclenyloxy when substituted are substitutedone or more times by R¹¹; R¹⁴ is independently selected from the groupconsisting of H or alkyl; and R¹⁵ is absent or selected from the groupconsisting of H and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl groups, each of which is optionally substituted with atleast one halo, —OH, —CN, —NO₂, —N(R¹¹)₂, and —S(O)_(p)R¹¹ and/or 1 or 2(═O); and q is 0 or 1, or a pharmaceutically acceptable salt thereof. 3.The compound according to claim 2, which has the formula

or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 3, or a pharmaceutically acceptable salt thereof, wherein R¹ isa ring selected from the group consisting of phenyl, pyrazole,pyrimidine, oxazole and isoxazole wherein said rings may be optionallysubstituted 1 to 3 times with substitutents selected from the groupconsisting of alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, —C(O)-amino; —C(O)-alkylamino,—C(O)-dialkylamino, —C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl,amino-C(O)—O-alkyl, amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, andheteroaryl, wherein said aryl and heteroaryl are optionally substituted1 to 3 times by alkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino,alkylamino, dialkylamino, alkoxy, and haloalkoxy; and R¹⁵ is absent. 5.The compound according to claim 2, which has the formula

or a pharmaceutically acceptable salt thereof.
 6. The compound accordingto claim 5 or a pharmaceutically acceptable salt thereof wherein R¹ is aring selected from the group consisting of phenyl, pyrazole, pyrimidine,oxazole and isoxazole wherein said rings may be optionally substituted 1to 3 times with substitutents selected from the group consisting ofalkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino, alkylamino,dialkylamino, —C(O)-amino; —C(O)-alkylamino, —C(O)-dialkylamino,—C(O)—OH, —C(O)—Oalkyl, amino-C(O)-alkyl, amino-C(O)—O-alkyl,amino-S(O)₂-alkyl, alkoxy, haloalkoxy, aryl, and heteroaryl, whereinsaid aryl and heteroaryl are optionally substituted 1 to 3 times byalkyl, haloalkyl, nitro, cyano, halo, hydroxyl, amino, alkylamino,dialkylamino, alkoxy, and haloalkoxy; and R¹⁵ is absent.
 7. Thefollowing compounds

or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising at least one compound of claim 1, or apharmaceutically acceptable salt, ester, solvate or prodrug thereof andat least one pharmaceutically acceptable carrier, adjuvant or vehicle,provided that when the composition is a liquid, aqueous composition oneor more solubility enhancing components are excluded with the exceptionof cyclodextrin.
 9. The pharmaceutical composition of claim 8, furthercomprising one or more additional therapeutic agents.
 10. Thepharmaceutical composition of claim 9, further comprising one or moreadditional therapeutic agents, wherein said additional therapeuticagents are selected from the group consisting of steroids,glucocorticosteroids, PDE-4 inhibitors, anti-muscarinic agents, musclerelaxants, cromolyn sodium, H₁ receptor antagonists, 5-HT₁ agonists,NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin IIreceptor agonists, β-blockers, long and short acting β-agonists,leukotriene antagonists, diuretics, aldosterone antagonists, ionotropicagents, natriuretic peptides, pain management/analgesic agents,anti-anxiety agents, anti-migraine agents, sedatives, NMDA receptorantagonists, alpha-adrenergics not including alpha-1 receptorantagonists, anticonvulsants, tachykinin (NK) antagonists, COX-2inhibitors, neuroleptics, vanilloid receptor agonists or antagonists,beta-adrenergics, local anaesthetic, corticosteroids, serotonin receptoragonists or antagonists, PDEV inhibitors, alpha-2-delta ligands,canabinoids and therapeutic agents suitable for treating heartconditions, psychotic disorders, or glaucoma.